TW200536530A - 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis c virus ns3 serine protease - Google Patents

Abstract

The present invention discloses novel compounds having HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

Description

200536530 9. Description of the invention: [Technical field to which the invention belongs] The present invention relates to novel hepatitis C virus ("HCVn) protease inhibitors, pharmaceutical compositions containing one or more such inhibitors, and the preparation of such inhibitors Methods, and methods of using such inhibitors to treat hepatitis C and related disorders. The present invention additionally discloses novel compounds containing a bicyclic P2 moiety as a HCV NS3 / NS4a serine protease inhibitor. This application U.S. Provisional Application No. 60 / 548,655 filed on February 27, 2004 ° [Prior Art] Hepatitis C virus (HCV) is a (+)-significant single-stranded RNA virus that has become non-A, non- -The main cause of hepatitis B (NANBH), especially in blood-related NANBH (BB-NANBH) (see, International Patent Application Publication No. WO 89/04669 and European Patent Application Publication No. EP 381 No. 216). Liver diseases caused by NANBH and other types of viruses, such as Hepatitis A virus (HAV), Hepatitis B virus (HBV), Hepatitis delta virus (HDV), Cytomegalovirus (CMV) and Ashton virus( (BV), and other forms of liver disease, such as alcoholism and primary biliary cirrhosis, are clearly different. Recently, HCV proteases required for polypeptide processing and viral replication have been identified, cloned, and expressed. (See, for example, U.S. Patent No. 5,712,145). This polyprotein of about 3000 amino acids, from the amino terminal to the carboxyl terminal, contains the shell-shell nucleic acid protein (C), the envelope proteins (E1 and Ε2), and several non-structural proteins (NS1 , 2, 3, 4a, 5a, and 5b). NS3 is a protein of approximately 68 kda 99028.doc 200536530, encoded by approximately 1,893 nucleotides of the HCV genome, and has two distinct functional sites: (a) silk The amino acid protease functional site consists of approximately 200 N-terminal amino acids; and (b) the RNA-dependent ATPase functional site at the c-terminus of the protein. The NS3 protease is considered to be of the chymotrypsin family Members because of similarities in protein sequence, overall three-dimensional structure and catalytic mechanism. Other chymotrypsin-like enzymes are elastase, factor X a, thrombin, trypsin, fibrin Leukolytic enzyme, urokinase, tPA and PSA. HCV NS3 serine protease is responsible for the proteolysis of peptides (polyproteins) at the junctions of NS3 / NS4a, NS4a / NS4b, NS4b / NS5a and NS5a / NS5b, and is therefore responsible for Four viral proteins are produced during viral replication. This creates HCV NS3 serine proteases, an attractive target for antiviral chemical methods. The compounds of this invention inhibit such proteases. They also mediate the processing of hepatitis C virus (HCV) polypeptides. It has been determined that the NS4a protein, a polypeptide of approximately 6 kda, is a cofactor for serine protease activity of NS3. NS3 / NS4 ^ < $ amino acid protease automatically cleaves the NS3 / NS4a junction to occur in the molecule (ie, cis), while other incision sites are processed in an intermolecular manner (ie, reverse) ° Analysis of the natural cleavage site of HCV protease It is shown that cysteine is present at p 1 and serine is present at PI, and these residues are strictly retained in the NS4a / NS4b, NS4b / NS5a, and NS5a / NS5b junctions. NS3 / NS4M ^ contains threonine at P1 and serine at PΓ. It is assumed that Cys-Thr substitution at NS3 / NS4a indicates that prosperous rather than reverse processing is required at this junction. See, eg, Pizzai et al. (1994) Proc. Natl. Acad. 99028.doc 200536530

Sci (USA) 91: 888-892, Failla et al. (1996) Folding & Design 1: 3 5-42. The NS3 / NS4a incision position is more tolerant to mutation generation than other positions. See, for example, Kollykhalov et al. (1994) J. Virol. 68: 7525-7533. It was also found that acidic residues in the upstream region of the incision site require effective incision. See, for example, Komoda et al. (1994) J_ Virol. 68: 735 1-7357 ° Inhibitors of HCV protease have been reported, including antioxidants (see, International Patent Application Publication No. WO 98/14181), a Peptides and peptide analogs (see, International Patent Application Publication No. WO 98/17679, Landro et al. (1997) Biochem. 36: 9340-9348, Ingallinella et al. (1998) Biochem. 37: 8906-8914, Llinas-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8: 1713-1718), an inhibitor based on the 70-amino acid peptide eglin (Martin et al. (1998) Biochem. 37: 1145 9-11468 'Inhibitor affinity is selected from human pancreas secreted trypsin inhibitor (hPSTI-C3) and minibody program (MBip) (Dimasi et al. (1997) J. Virol. 71: 7461- 7469), cVHE2 (an lf-camelized `` variable functional site antibody fragment) (Martin et al. (1997) Protein Eng. 10: 607-614) 'and αΐ-anti-chymotrypsin (ACT) (Elzouki Et al. (1997) J. Hepat. 27: 42-28). A ribozyme has recently been revealed which is designed Selectively destroys hepatitis C virus RNA (see, Bio World Today 9 (217): 4 (November 10, 1998, 1998)). See also PCT Publication No. WO 98, published on April 30, 1998 / 17679 (incorporated in Vertex Pharmaceuticals); 99028.doc 200536530 WO 98/22496 (F. Hoffmann, La Roche AG) published on May 28, 1998; and WO 99 published on February 18, 1999 / 07734 (Boehringer Ingelheim Canada Ltd.) HCV has been involved in cirrhosis of the liver and causes hepatocellular carcinoma. At present, patients suffering from HCV infection have a poor prognosis. HCV infection is more difficult to treat than other forms of hepatitis. Because of the lack of immunity or reduction associated with HCV infection, current data point to a survival rate of less than 50% within four years after the diagnosis of cirrhosis. Patients diagnosed with localized resectable hepatocellular carcinoma have 10-30 ° /. Five-year survival rate, while those with localized unresectable hepatocellular carcinoma have a five-year survival rate of less than 1%. Reference is made to WO 00/59929 (U.S. Patent No. 6,608,027, Trustee: Boehringer Ingelheim (Canada) Ltd .; issued October 12, 2000), which discloses peptide derivatives having the formula:

Reference VIII. He & 1 et al., 8711, 81, 1000-1002 (1999) describe the synthesis of bicyclic analogs of inhibitors of HCV NS3 protease. The compound disclosed therein has the formula: 99028.doc 200536530

Reference is also made to W. Han et al., Bioorganic & Medicinal Chem. Lett, (2000) 10,711-713, which describes certain α-amidines, α- 0¾ esters containing allyl and ethyl functionality And α-Di-K.

See also WO 00/09558 (Trustee: Boehringer Ingelheim Limited; published February 24, 2000), which discloses peptide derivatives of the formula:

Various elements are defined herein. Examples of compounds in this series are:

99028.doc -10- 200536530 See also WO 00/09543 (Trustee Boehringer Ingelheim Limited; published February 24, 2000), which reveals a peptide derivative of the formula: / 3 R6

OH where various elements are defined herein. Examples of compounds in this series are: ch3 p H3C / CH3 H3C " ^ SXs " 〇x H3C \ / CH3

Λ ch2

JOH also refers to US Patent No. 6,608,027 (Boehringer Ingelheim Canada) which discloses the following types of NS3 protease inhibitors: 99028.doc -11-200536530 丨 21 22

Various sections are defined herein.

Current treatments for hepatitis C include interferon-a (iNFa) and a combination of ribavirin and interferon. See, for example, Beremguer (1998) Proc. Assoc. Am. Physicians 110 (2): 98-112. These treatments suffer from low sustained response rates and often have side effects. See, for example, Hoofnagle et al. (1997) N. Engl j Med. 336: 347. There is currently no vaccine available for HCV infection. Progress reference is made to WO 01/74768 (trustee: Vertex Pharmaceuticals Inc) published on October 11, 2001, which discloses certain compounds of the following general formula (R is defined herein) as NS3-filaments of hepatitis C virus Amino acid protease inhibitors:

The specific compound disclosed in the previously mentioned WO 01/74768 Φ sister formula: has the following 99028.doc 200536530

PCT Publications WO 01/77113; WO 01/081325; WO 02/08198; WO 02/08256; WO 02/08187; WO 02/08244; WO 02/48172; WO 02/08251; and January 18, 2002 U.S. Patent Application No. 10 / 0052,386, which is pending, discloses various types of peptides and / or other compounds that are NS3-serine protease inhibitors of hepatitis C virus. The disclosures of these applications are incorporated herein by reference in their entirety. Novel treatments and therapies for HCV infection are needed. There is a need for compounds that can be used to treat or prevent or ameliorate one or more symptoms of hepatitis C. What is needed is a method to treat or prevent or ameliorate one or more symptoms of hepatitis C. There is a need for a method for modulating the activity of serine proteases, particularly HCV NS3 / NS4a serine proteases, using the compounds provided herein. Methods of modulating the processing of HCV polypeptides using the compounds provided herein are needed. [Summary of the Invention] In many specific embodiments of the present invention, new types of HCV protease inhibitors, pharmaceutical compositions containing one or more such compounds, and preparations of pharmaceutical compositions including one or more such compounds are provided. Method, and the use of one or more of these compounds or one or more of these formulations, treatment or pre-treatment 99028.doc -13-200536530

R2 A method to prevent HCV or to improve the symptoms of -or polyhepatitis. Methods are also provided for modulating the interaction of HCV polypeptides with protease. Among the compounds disclosed herein, compounds that inhibit HCVNS3 / NS4 ^ amino acid protease activity are preferred. The invention discloses a compound or an enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate of the compound, or a pharmaceutically acceptable salt or solvent of the compound Compound or vinegar, the compound has a common structure shown in structure gl: 〇R1 Formula 1 wherein: R1 is Η, ⑽, NRH chr9r10, where r8, Ri can be the same or different, and are selected from H, alkyl_ , Alkenyl_, alkynyl_, arylheteroalkylheteroaryl, cycloalkyl, heterocyclyl, arylalkyl, and heteroarylalkyl: 20% of the group, or R, R1 in NRV0 ° Connected to each other such that NR = forms a four to eight-membered heterocyclic ring, while R9 in chr9r10 is also connected to each other such that CHR9RlG forms a four to eight-membered cycloalkyl group; / and R3 may be the same or different 'respectively Selected from H, xyl, heteroalkyl, rare earth heterofluorenyl, alkynyl, heteroacyl, cycloalkyl, heterocyclyl, aryl, 99028.doc -14- 200536530

A group consisting of aralkyl, heteroaryl, and heteroaralkyl; γ is selected from the following:

Where G is NH or 〇; and R15, R16, R17, R18, r19, r2021, R, R22, R23, R24, and R25 may be the same or different, and are selected from H, alkyl, heteroalkyl, and olefin Group consisting of aryl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, or (i) R17 and R are connected to each other , To form a two to eight-membered cycloalkyl or heterocyclic group; (丨 丨) Similarly, to each other, to form a four to eight-membered heterocyclic group; ㈣ Similarly 99028.doc -15-200536530 Ground, R and R are connected to each other , To form a four- to eight-membered heterocyclic group; (iv) Similarly, R and RG are connected to each other to form a four-to-eight-membered heterocyclic group '· (V) Similarly, "" and Chem 23 are connected to each other to form three To eight-membered cycloalkyl or four to eight-membered heterocyclyl; and (vi) Similarly, R24 and R25 are connected to each other to form a three to eight-membered cycloalkyl or four to eight-membered heterocyclyl; wherein each Each alkyl group, aryl group, heteroaryl group, cycloalkyl group or heterocyclic group may be unsubstituted, or may be substituted with one or more parts, respectively. From hydroxyl, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, amido, alkylamino, arylamino, alkanesulfonyl, arylsulfonyl, sulfonamide Alkyl, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, ketone, carboxyl, alkoxycarbonyl, carboxyamido, carboxycarbonylamino, alkoxycarbonyl A group consisting of oxy, alkallowyl, arylureido, sulfoxane, cyano, and nitro groups. In the definitions mentioned above, the preferred alkyl group is composed of from 1 to 10 carbon atoms. The preferred alkenyl or alkynyl group is composed of 2 to 10 carbon atoms, the preferred ring # alkyl group is composed of 3 to 8 carbon atoms, and the preferred heteroalkyl, heteroaryl or heterocyclic group is (Heterocyclyl) has 1 to 6 oxygen, nitrogen, sulfur, or scale atoms. The compound represented by Formula 1, by itself or mixed with one or more other suitable formulations disclosed herein, can be used to treat diseases such as It is a case of wHcv, HIV, AIDS (Acquired Immunodeficiency Syndrome) and related disorders, and can be used to modulate the activity of hepatitis C virus (HCV) protease, prevent HCV, or improve hepatitis C _ Or multiple symptoms. The compounds of the present invention, as well as pharmaceutical compositions or formulations including such compounds, can be used to perform such adjustments, treatments, preventions, or ameliorations. Without being limited by theory, I believe Hcv protease 99028.doc -16- 200536530 May be NS3 or NS4a proteic acid. The compound of this invention can inhibit this kind of eggplants. The daggers can also regulate the addition of hepatitis C virus (HCV) polypeptides. In a specific embodiment, the present invention discloses a compound represented by Structural Formula 1 or a pharmaceutically acceptable salt, vehicle or ester thereof, wherein various parts are as defined above.

In another specific embodiment, R1 is NR9R10, and R9 is η, and R10 is H or R14, wherein R14 is fluorene, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl- Aryl, alkyl-heteroaryl, aryl-alkyl, alkenyl, alkynyl, or heteroaryl-alkyl. In another specific embodiment, R14 is selected from the group consisting of: VH, γΜθ, '^ 1-5,

99028.doc -11 a 200536530

Me

In another embodiment, R2 is selected from the group consisting of:

99028.doc -18- 200536530

In a further specific embodiment, R3 is selected from the group consisting of:

cf3

/ X ^ NHR32 99028.doc -19- 200536530

Wherein R31 is OH or 0-alkyl; and R32 is Η, C (0) CH3, C (0) 0tBu or C (0) N (H) tBu. In additional embodiments, R3 is selected from the group consisting of:

99028.doc -20- 200536530

In another specific embodiment, G is NH.

In a further specific embodiment, Y is selected from the following:

99028.doc -21-200536530

Wherein R15, R16, R17, R18, R19, R20, Rh, R22, r23, R24 and R25 are selected from H, alkyl, heteroalkyl, fluorenyl, heterodiluted, fastyl, heteroalkynyl, cycloalkyl Group, heterocyclyl, aryl, aralkyl, heteroaryl and heteroaralkyl, or (i) R17 and R18 are connected to each other to form a three to eight membered cycloalkyl or heterocyclic group; (ii) the same Ground, R15 and R19 are connected to each other to form a four- to eight-membered heterocyclic group; (iii) Similarly, R15 and R16 are connected to each other to form a four-to-eight-membered heterocyclyl, and (iv) similarly 'R 5 and R2 G Connected to each other to form a four to eight membered heterocyclyl; each of the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl groups may be unsubstituted, or may be divided into one or more parts, as required Substituted, this moiety is selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, amidoamino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl Alkyl, sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, ketone, carboxyl, alkoxycarbonyl, carboxyamido, alkoxycarbonylamino , Aryloxycarbonyl group, a ureido group consisting of alkyl, aryl ureido group, _, cyano and nitro groups. In additional specific embodiments, this section:

Is selected from the following:

99028.doc -22- 200536530

Γ32 is selected from the group consisting of: human γγ \ γγ,

In a further specific embodiment, γ is selected from:

99028.doc -23-200536530

In additional specific embodiments

, This part R ^ 3 d22 r2Ck

r25X is selected from the following structures ...

In additional specific embodiments, R1 is a group of NHR columns. 99028.doc 200536530

99028.doc -25- 200536530

R3 is selected from the group consisting of:

cf3 co2h

c〇2h -26- 99028.doc 200536530

This part:

And γ is selected from:

99028.doc -27- 200536530

Other specific examples of the present invention disclose the compounds shown in Table 1. Table 1

99028.doc -28- 200536530 99028.doc

, Nt " tr ya y 0 k 0

nh2

° V ^ N o.n / 〇 T / s 〔n ~ nh

nh2

V

29-

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〇 ^ γΑ ^ ΝΗ2 々 人 々: o ^, 0ΥΝΗ ^ NH '' 〇γΝΗ ^ QNH Vv > LS ° T; 0¾ 0 λNH L α ^ τ " > ls ^ T; h C $ A person: 1 cxi &! > Ls ^ ThNH】 Ya '^ nh2 Vi / VN α ^, human pose NΗ | \ NH2 > V ^ 〇 ° > (^ γ-, eight b ^ \ 〇〇rNH 99028.doc 32- 200536530

99028.doc

-33-200536530 99028.doc

ρ ° γΝ

nh2

νη2

0 ~ NH

〇 ~ ΝΗ

Ν

ρ ° γΝ

Η

〇 Ya ΝΗ II,

Η Ν1 Ο

, NΗ

Ο k Ο Ο ~ ΝΗ

ΝΗ2

.ΝΗ

ΝΗ2, ΝΗ,

0ΥΝ 〇Νχ / 〇 Τ / S

Η

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99028.doc NH 1 not O ^ NH > 〇Ν ^ γΝΗ 1 not 0 u /-\ ,, () u nh > 〇να ^ νη 1 not 0γΝΗ I / st〇N ^ rNH 1 not 1 O ^ NH / γζ ^ γΝΗ 1 不 'γΛ ^ -ΝΗ2 V violent 0 ^ ΝΗ X-Jh 0 ^ Λ ^ ΝΗ2 o ^ / NH ^ StN ^ VNH | not 〇 ^ .nh / stN ^ r-NH 1 not storm NH Χ 1 不 o ^ nh XjA ^ nh 1not to do, O ^ NH ^ St〇N ^ YNH 1 not x ° τ; 1 1 not 1 35- 200536530

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0 k ο

nh2

nh2

0 k 0 II

H

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〇 丫 N

nh2

〇x / NH

NH2,

^ NH

p ° YN

N'I I Ϊ V

ο ° γΝΗ ||

0 Yab

H

0 k 0

Canton 00

NH2

0 k 0 meaning 0

nh2

N,

X ίτ 丫 > r O V 0 people 〇% 「

0 ah NH II 40- 200536530

Storm o ^ nh cr II Storm X 1 1 X 1 〇 ° γΝΗ II όχ Good H 1,1 Storm 〇..〇VH croc II ^ NH 1 1 Storm x of? 1 V ~ III 〇5 ^ " II 〇5 ^ NH 1 1 1 > ^ 0 ° Vp 〇, 〇 ° YNH F, s, N ~ nh 1 X one eight, > > ^ 〇〇Vp 丫 Η FA ^ > ^ 〇〇Vp ox / o ° YNH F as'X A ^ V ^ o0 〇.〇 ° YNH F 99028.doc -41-200536530

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^ Vsf0 ° ynh UCn ~ ^ nh II CX ^ TRX NH V is II points 11 rN ^ i ° rH ii Xs ^ xNH 〇.p ° YNH 1 cr, T II ^ rsX 4: 1 1 〇 ° rNH ii 6X ΟγΝΗ Μ λx \ 0 γNH d ^ x ill 〇, .〇 ° YNH 1, human n eight rNH 1 1 XV, 1 rrl ° rNH UC / γII ° V〇 ° γΝΗ < QQN] Nh II ^ TRT ^ Ν ° ° rNH U ^ N H II 〇 ,, 〇 ° rNH 1 1 99028.doc 45- 200536530

Additional compounds are also provided according to the invention in Table 1A: Table 1A

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> ν ^ 〇ο γ Me-ο ^ τ: Η > ^ Λ〇◦ γ factory \ 、, hYH Me ^ N ^ sx ^ 5xc! jJH > V ^ o◦ 丫 v ηΛΝΗ u ^ NWv > V ". 0 _v Me ° γΝΗ vV ^ > V ". 0 v Me ° γΝΗ ^ 4 Know rV ^ > V ^. . -v Me ° γΝΗ A > ^ 〇0 Y Me ° γΝΗ M ^ NH > V ^ o〇Y Me ° γΝΗ ^ < ^ NH: V〇ov Me ° γΝΗ As used above and disclosed here In the content, unless otherwise specified, it should be understood that the following terms have the following meanings: "Patient" includes humans and animals. "Mammalian" means humans and other mammals. Π alkyl means that may be Straight or branched aliphatic hydrocarbon group and includes about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred Alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branching means one or more as low as 99028.doc -50- 200536530

An alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. π lower carbon number alkyl means a group having about 1 to about 6 complete atoms in the chain 'which may be linear or branched. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents, which may be the same or different. Each substituent is independently selected from the group consisting of alkyl, alkyl, aryl, Cycloalkyl, cyano, mesityl, alkoxy, thiothio, amine, ΝΝΗ (institutional), _ΝΗ (cycloalkyl), _Ν (alkylh, _ν (alkylh, carboxy, and alkyl) The group formed. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tertiary-butyl. Alkenyl means containing at least one carbon-carbon double bond Aliphatic hydrocarbon group, and it may be straight or branched and include from about 2 to about 15 carbon atoms in the chain. The preferred dilute group has about 2 to about 12 in the chain Carbon atoms; and more preferably from about 2 to about 6 carbon atoms in the chain. Branched means one or more low carbon number alkyl groups, such as methyl, ethyl or propyl, and linear An alkenyl chain is attached. "Low carbon number alkenyl" means a group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched., And substituted alkenyl It means that the alkenyl group may be substituted by one or more substituents, which may be the same or different, and each substituent is selected from halide, alkyl, aryl, cycloalkyl, cyano, Non-limiting examples of alkenyl groups consisting of ethylenyl, oxo, and canyl include ethylene, propenyl, alkenyl, 3-methylbutenyl, and n-pentenyl , Octenyl, and decyl. Alkynyl aliphatic hydrocarbons containing at least one carbon-carbon triple bond on the 4th can be straight or branched, and include about 2 to about 99,028.doc in the chain. -51-200536530 about 15 carbon atoms. Preferred alkynyl groups have about 2 to about i2 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched Means that one or more lower carbon number alkyl groups, such as methyl, ethyl or propyl, are attached to a straight alkynyl chain. "Low carbon number alkynyl" means having about 2 to about A group of about 6 carbon atoms, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, and 3-methylbutane Alkenyl. The term "substituted alkynyl" means that the alkynyl group may be substituted with one or more substituents, which may be the same or different, each substituent being selected from alkyl, aryl and A group consisting of a cycloalkyl group. "Πaryl" means an aromatic monocyclic or polycyclic ring system, including about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be substituted as desired with one or more `` ring system substituents π, which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl And naphthyl. Heterocyclyl " means an aromatic monocyclic or polycyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 1 G ring atoms, wherein-or more The% atom is an element other than carbon, such as nitrogen, oxygen, or sulfur, alone or separately. Preferred heteroaryls contain about 5 to about 6 ring atoms. If desired, the " ring system substituent " may be substituted for " heteroaryl ", which may be the same and different as defined herein. The term "acyl" or "thia" before the heteroaryl root name means that at least one nitrogen, oxygen, or sulfur atom, respectively, is formed into a) ring atom. If necessary, the nitrogen atom of the heteroaryl group can be oxidized to a relative ~ t compound Non-limiting examples of suitable heteroaryl groups include stilbyl, pyridyl, furyl, thienyl, pyrimidinyl, pyridone (including N 'substituted pyrrolidone 99028.doc -52- 200536530), Isoxazolyl, isothiazolyl, humazolyl, thiazolyl, η-sialyl, furyl, pyrrolyl, pyrazolyl, triazolyl, 12,4-thiadiazolyl, Dacrotyl, quinazolinyl, stilbyl, oxindole, imidazo [1,2-a] ° than σ 疋, _ α and [2,1-b] salyl, benzene Benzene, sigmadol, sigmadol, azindolyl, benzimidazolyl, benzothienyl, quinolinyl, amidol, thienopyryl, quinazolinyl, thienopyrimidinyl, pyrrol Pyridinyl, imidazolodinyl, isoquinolinyl, benzoazinyl, ^, trisynyl, benzothiazolyl and the like. "Heteroaryl, also means partially saturated Heteroaryl Points, such as for example, a tetrahydroisoquinoline group, tetrahydroquinolyl and the like. "Aralkyl" or "aralkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls include low carbon number alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 3-phenethyl, and naphthylmethyl. The bond to the parent moiety is through an alkyl group. `` Alkylaryl '' means alkyl- Aryl-groups in which the alkyl and aryl groups are as previously described. Preferred alkaryl groups include low carbon number alkyl groups. Suitable non-limiting examples of aryl groups are tolyl. The bond to the parent moiety is through an aryl group. "Cycloalkyl" means a non-aromatic mono- or polycyclic ring system, including about 3 to about 10 carbon atoms, preferably about 5 to about 1 0 carbon atoms. Preferred cycloalkyl radicals contain about 5 to about 7 ring atoms. If desired, one or more "ring system substituents" may be substituted for "cycloalkyl", which may be the same or different And as defined in this article. Non-limiting examples of suitable monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable polycyclic cycloalkyl include naphthyl, naphthyl, 98028.doc 53-200536530, adamantyl and the like, and partially saturated species such as, for example, hydroindenyl , Tetrahydronaphthyl and its analogs. Halogen or halogen refers to fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine and bromine. "Ring system substituents" means substituents attached to an aromatic or non-aromatic ring system, which, for example, replaces the chlorine available on the ring system. The ring system substituents may be the same or different, and are selected separately From alkyl, alkenyl, alkynyl, aryl, heteroaryl, aromatic, aryl, heteroaryl, heteroaryl, diaryl, heteroarylalkynyl, alkylheteroaryl, hydroxyl, hydroxyalkane Base, alkoxy, aryloxy, aralkyloxy, fluorenyl, arylfluorenyl, sulfonyl, alkoxy, cyano, and retarder: alkoxy, aryloxy, aryloxy, aryl Fluorenyl, aryl, sulfonyl, heterosulfenyl, alkylthio, arylthio 'heteroarylthio, aralkylthio, heteroarylthio, cycloalkyl, heterocyclic, _C (= N _ Called legs 2, leg evaluation) Gu2, _c (= called N position), ΥιΥ2Ν_, I from burning base_, YANC ^ O)-, YlYlNS〇2 · and _s〇2NYiY2, where I And h may be the same or different, and are respectively selected from the group consisting of hydrogen, alkyl, alkynyl, 1-cycloalkyl, and fluorenyl. "The ring system silk group" may also mean a single part, and at the same time Instead of two adjacent carbon atoms on the ring system Two available hydrogens (one on each carbon. Examples of such moieties are methylenedioxy ^ ethylenedioxy, alkoxy) and their analogs, which form like this

The L j Ο ·· left foot portion and the "heterocyclyl group" (iv) aralkyl of fresh t㈣ monocyclic or rural comprises from about 3 to about 10 ring atoms, Mi ^ ,, light shield workers willing Shang Bian Chinese f "Soil piece goods About 5 to about 10 ring atoms, where in the ring system W—or more atoms are elements other than carbon 99028.doc -54- 200536530, such as lice, oxygen, or sulfur, alone or in combination. / ^ Ia ^. There are no adjacent gas and / or sulfur atoms in the ring system. The hetero-ring group of y 包括 includes about 5 to about 61% of atoms. In the heterocyclic root name, another ... Perazine, i or thio, means to separate out > a nitrogen, oxygen or sulfur atom and attack as% atom. Any miscellaneous bribes can be protected, such as, for example, the nr (CBz), -N (T ° S) group, and the like; such protection is also considered as part of the present invention .笪 ... Γ depends on one or more, ring system instead of soil instead of heterocyclic group ", which can be irrespective of the phase π, and as in this article = fixed two. If necessary, the heterocyclic group or Oxidation of a sulfur atom to a hafnium oxide, s oxide, or s, s dioxide. Non-limiting examples of suitable monocyclic heterocyclic soils include hexachloromethyl, hexachloromethyl, hexachloromethyl, morpholinyl, Thiomorphinyl " selenium, alkyl, tetrakilan, tetrahydrotyl, lactam, pyridine, and the like. It should be noted that the impurities contained in the ring system of the present invention Among the atoms, there is no fluorene group on the carbon atom adjacent to the disk N, 0 or S 'and no group on the carbon atom adjacent to other heteroatoms. For this reason, for example in a ring: 4 Jk

And: _OH is directly attached to the carbons labeled 2 and 5. It should also be noted that the inter-g configuration form 'looks like, for example, the following:

ΰΗ rr

I Η is considered equivalent in certain embodiments of the invention 99028.doc -55- 200536530 "Fast-burning" means an alkynyl-alkyl- group, where the alkynyl and alkyl groups are as previously Described. Preferred alkynyl groups contain low-carbon alkynyl and low-carbon alkyl groups. The parent moiety is bonded via an alkyl group. Non-limiting examples of suitable alkynyl groups include propargyl Methyl. "Heteroaryl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a low carbon number alkyl group. Non-limiting examples of suitable aralkyl groups include pyridinylmethyl and quinolin-3-ylmethyl. The bonding of the parent moiety is through an alkyl group. `` Πhydroxyalkyl '' means HO-alkyl-yl Groups, wherein the alkyl group is as previously described. Preferred hydroxyalkyl groups contain low carbon number alkyl groups. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. 'Means HC (O)-, alkyl-c (0)-or cycloalkyl-c (0)-groups, where the various groups are as previously described. The bonding of the parent moiety is through a carbonyl group. The fluorenyl group contains a low carbon number alkyl group. Non-limiting examples of suitable fluorenyl groups include methyl fluorenyl, ethyl fluorenyl, and propyl fluorenyl. 11Arylfluorenyl means aryl-C (0)- A group wherein the aryl group is as previously described. The bonding of the parent moiety is through a carbonyl group. Non-limiting examples of suitable groups include benzamyl and i-naphthyl. "Alkoxy" means an alkyl group, wherein the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, 2oxy, n-propoxy, iso Propoxy and n-butoxy. The bonding of the parent moiety is through an ether oxygen. Σ "Aryloxy" means an aryl-0- group, where the aryl group is as described in j π Non-limiting examples of suitable aryloxy groups include alkoxy and Guan 99028.doc -56- 200536530. The bonding of the parent moiety is through an ether oxygen. `` Aralkoxy '' means Aralkyl groups in which the aralkyl group is as described previously. Non-limiting examples of suitable aralkyloxy groups include benzyloxy ^ and 1- or 2-naphthylmethoxy. Bonds of the parent moiety The junction is via ether oxygen. "Alkylthioπ means an alkyl-S- group, wherein the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bonding of the parent moiety is via sulfur. '' Arylthio f 'means an aryl-S- group, where the aryl group is as described previously. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bonding of the parent moiety is via sulfur. "πaralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. A non-limiting example of a suitable aralkylthio group is benzylthio. The parent Bonding is via sulfur. "Alkoxycarbonyl" means an alkyl-0-C0- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond 0 of the parent is through several bases. "'Aryloxycarbonyl'" means an aryl-o-c (o)-group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl. The bonding of the parent is via Weki. ^ πaralkoxycarbonyl '' means an aralkyl-o-c (o)-group. A non-limiting example of a suitable aralkyloxycarbonyl; group is benzyloxycarbonyl. The bonding of the parent moiety is through a carbonyl group. '' Alkanesulfonylπ means an alkyl-s (o2)-group. Preferred groups are those in which the alkyl group is a lower carbon number alkyl group. The bonding of the parent moiety is via a sulfonium 99028.doc -57- 200536530. The radical means an aryl_§ (〇 2)-group. The bonding of the parent moiety is via ruthenium.

11 The term "substituted" means the replacement of one or more hydrogens on the indicated atom with a person selected from the specified group, subject to the condition that the normal valence of the indicated atom is not exceeded under existing conditions, and This substitution produces a stable compound. As long as such a combination results in a stable compound, the combination of substituents and / or variables is permitted. "Stable compound" or "stable structure" means that a compound is strong enough to withstand It is isolated from the reaction mixture to a useful degree of purity and formulated into an effective therapeutic agent. When referring to the number of non-substituents, compounds, mixed preparations and the like, use the noun "one or more, or, at least one" according to the preceding and following meanings, or And the maximum number of substituents, compounds, combined preparations and the like that are chemically or physically acceptable. Such techniques and knowledge are within the scope of those skilled in the art. "Substitute as needed"-The word means that it can be optionally substituted with a specified group, root, or moiety. ~ Avoided / knife, isolated, or "is an isolated form of a" compound "meaning the physical state of the compound after isolation from a synthetic process or natural source or combination thereof. &Quot; purified" or " In a purified form, the compound word two means the physical state after purification and payment of the compound described or familiar with the art, which has sufficient purity, as described in the text or The standard analysis techniques familiar to this artist are special. 99028.doc -58- 200536530 It should also be noted that in the text, plans, examples, and tables of this article, any carbon or heteroatom with an unsaturated valence has a hydrogen atom (group) to saturate the valence. When a functional group in a compound is said to be, protected, this means that the group is in a modified form, and when the compound is subjected to a reaction, unwanted side reactions are excluded at the protected position. Appropriate protecting groups will be recognized by those skilled in the art, and by reference to textbooks such as, for example, T.w. Greene et al., Protective Grós in Organic Synthesis (1991), Wiley, New York. When any variable (eg, aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in Formula 1, its definition at each occurrence is independent of its definition at every other occurrence. As used herein, the term " composition " is intended to include products that include specific ingredients in specified amounts, as well as any products that result directly or indirectly from a combination of specific ingredients in specified amounts. This text is also expected to Prodrugs and vehicles of the compounds of the invention. As used herein, the term "prodrug," stands for a compound that is a drug precursor, δ undergoes chemical transformation through metabolism or chemical processes when administered to an individual To produce a compound of formula 1, or a salt and / or vehicle thereof. In Ding Higuchi * v ·

Stella, Pro-drugs as Novel Delivery Systems (1 987) 14 of the A.C.S. Symposium Series, and in Bioreversible CarHers in Drug Design, (1987) Edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press A discussion of prodrugs is provided, both of which are incorporated herein by reference. 99028.doc -59- 200536530 " Vehicle " means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonding, including hydrogen bonding. In some instances, the vehicle will be capable of separation, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. " Vehicle " includes both solution phase and separable media. Non-limiting examples of suitable vehicles include ethanolate, methanolate, and the like. ", Hydrate" is a hydrate in which the solvent molecule is h2o. π effective 1 "or" therapeutic content "means that the content of the compound or composition of the present invention described is effective in inhibiting CDK (group), and thus produces the desired treatment, improvement, Suppressive or preventive effect. Compounds of formula 1 which form salts are also within the scope of the invention. When referring to a compound of formula 1 herein, it is understood that salts are also included unless otherwise specified. As used herein, the term "salt (class)", represents acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when the formula 1 The compound contains a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as but not limited to a carboxylic acid, which can form a zwitterionic internal salt "), and also includes those used herein Within the word salt (class). Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts may be used. The salts of the compound of formula 丨 can be formed, for example, by reacting a compound of formula 丨 with a quantitative acid or test, such as an equivalent amount, in a medium in which salts are precipitated or in an aqueous medium, followed by freeze-drying. Representative acid addition salts include acetate, ascorbate, benzoate, besylate, bisulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, Fumarate, hydrochloride, bromine 99028.doc • 60- 200536530 acid, hydroiodate, lactate, maleate, methanate, naphthoxate, Zoate, oxalate, erate, propionate, salicylate, succinate, tartrate, thiocyanate, tosylate (also known as tosylate), and similar Thing. Thus, for example, P. Stahl et al., Camille G. (ed.) Handbook of Pharmaceutical Salts. Properties, Selection and Use, (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; p. Gould,

International J. of Pharmaceutics (1986) 33 201-217;

Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange BOOk (Food & Drug Administration, Washington, DC on its web site) discusses general Acids that are considered suitable for use in the formation of pharmaceutically useful salts from basic pharmaceutical compounds. These disclosures are incorporated herein by reference. Representative test salts include ammonium salts, metal test salts such as sodium, bell and bell salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (such as organic amines), such as bicyclic Hexylamine, tertiary-butylamine, and salts with amino acids such as arginine, lysine, and the like. Preparations can be used for the quaternization of experimental nitrogen-containing groups, such as low carbon number alkylates (e.g. methyl, hydrocarbyl and butanol, bromine and iodine), dialkyl sulfates (e.g. diethyl sulfate) , Diethyl and dibutyl), long chain iides (such as decyl, dodecyl and stearyl chloride, bromine and iodine), aralkyl iides (such as benzyl and phenethyl bromide), and other. For the purposes of the present invention, all such salts intended to be pharmaceutically acceptable 99028.doc • 61-200536530 Acid salts and basic salts are within the scope of the present invention, and all acid and bases are considered The salts of the formula are equal to the free form of the corresponding compound. The pharmaceutically acceptable esters of the present invention include the following groups: The carboxylic acid esters obtained by the saponification of the saponyl group, the non-carbonyl portion of the carboxylic acid portion of the ester is selected from Linear or branched alkyl (e.g. ethenyl, n-propyl, tertiary-butyl or n-butyl), alkoxyalkyl (e.g. oxymethylbenzoyl (e.g. f-based) , Aryloxy group (such as phenoxymethyl), aryl (such as phenyl substituted with halogen, Cl_4 alkyl or C 丨 _4 alkoxy or amine, if necessary); (2) acid 0 Purpose, such as phosphonium aryl or aryl fluorenyl (eg,% methyl succinyl); (3) amino esters (such as L 'amine fluorenyl or [_ isoleucine pentyl] phosphonate and ⑺ Mono-, di- or tri-phosphoric acid esters. It can be further advanced by, for example, Cm. Known or its reactive derivative, or signed-\ λ ±: ^ Hunter 2,3_one (C6 · 24) fluorenyl Glycerol, which esterifies phosphates. Compounds of Formula 1, and their salts, solvates, esters, and prodrugs, can exist as tautomers (eg, amidine or imine ethers obtained herein) To make all such tautomers Part of the attempt to make all stereoisomers (such as male isomers, optical Isomers and their analogs), such as those that may occur due to asymmetric carbons on the various substituents, including enantiomeric forms (even moons can occur in the absence of asymmetric carbons), rotational conformation forms, Both atropisomers and diastereoisomeric forms are within the scope of the present invention, as are positional isomers (such as, for example, 4+ and 30 decayl). The compounds of the present invention are individually Stereoisomers can be, for example, substantially non -... 99028.doc -62- 200536530 isomers, or can be mixed into, for example, racemates, or with all other, or other stereoisomers derived. This The chiral center of the invention may have an s or r-configuration, as defined by the IUPAC 1974 recommendation. The use of nouns, salts,, and medicaments, "ke medicine" and the like, is intended to be equivalent Enantiomers, stereoisomers Compounds, rotamers, tautomers, positional isomers, racemates, or prodrug salts, vehicles, and prodrugs. An attempt was made to combine compounds of formula 1 and salts and vehicles of compounds Polymorphic forms of and prodrugs are included in the present invention. It should be understood that the utility of the compounds of formula 1 in the therapeutic applications discussed herein can be applied to each compound itself or to a mixture or combination of one or more compounds of formula As explained, for example, in the immediately following paragraph. The same understanding also applies to pharmaceutical compositions (groups), including such compounds or groups of compounds, and methods (men) of treatment involving such compounds or groups of compounds. According to The compounds of the present invention may have pharmacological properties; in particular, the compound of formula 1 may be an inhibitor of HCV protease, each compound itself or-· = multiple compounds of formula 1, which may be selected from-or multiple compounds of formula 1 Compounds (groups) of compounds can be used to treat diseases such as HCV, HIV, (Acquired Immunodeficiency Syndrome) and related conditions, and can be used to regulate the activity of c_ Holy liver disease (HCV) protease, Or preventing one or more symptoms of hepatitis C. The compound of formula 1 can be used to manufacture a medicament for treating a condition associated with HCV egg autoenzyme. For example, the method includes intimate contact of a compound of formula 1 with a pharmaceutically acceptable carrier. In other specific embodiments, the present invention provides a pharmaceutical composition, including 99028.doc -63-200536530: the compound or compound group of the present invention as an active ingredient. The pharmaceutical composition includes the following: pharmaceutically acceptable carrier diluents, excipients or carriers (herein, from # & 1 ^,

Is called the carrier material). Because of its HCV inhibitory activity, this type of pharmaceutical group has a combination of mandarin and azalea, and its mouthfeel has utility in treating hepatitis C and related diseases. In another specific embodiment, the present invention discloses a method for preparing a pharmaceutical composition including a compound of the present invention as an active ingredient. In the pharmaceutical composition and method of the present invention, live keshiba, s # μ t 陉 成 刀 通 * will be mixed with an appropriate carrier material and administered 'appropriately select the carrier material for the desired form of administration , That is, oral tablets, capsules (filled with solids, filled with semi-solids or filled with liquids), combined powders, oral gels, ugly agents, dispersible granules, sugar polysaccharides, suspension liquids and the like, And in line with traditional pharmaceutical habits. Example > Regarding oral administration of tinctures or capsules, the active tincture component can be mixed with any pharmaceutically acceptable inert carrier which is non-toxic orally, such as lactose, sodium powder, sugar, cellulose, hard Magnesium stearate, sulfur, talc, mannitol, ethanol (liquid form), and the like. In addition, when desired or needed, suitable binders, lubricants, disintegrating agents, and coloring agents can be incorporated into the mixture. Powders and lozenges may include from about 5 to about 95% of the composition of the invention. Suitable binders include gluten flour, gelatin, natural sugars, corn sweeteners, natural and synthetic gums, such as alara gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, and bad. Among the lubricants mentioned, boric acid, sodium benzoate, sodium acetate, sodium gasification and the like which can be used in these dosage forms are mentioned. Disintegrants include starch, methyl cellulose, guar gum, and the like. 99028.doc -64- 200536530 may also include sweeteners and colorants and preservatives where appropriate. Some of the terms mentioned above, i.e., disintegrants fengan phase /, tritium / sulfonate, binders and the like are discussed in more detail below. =, = Mingzhi composition can be formulated in the form of sustained release, so that the rate of component or active ingredient release is controlled, and large curative effect, namely HCV inhibitory activity and the like. Appropriate dosage forms include multi-layered lozenges,

Two v = component controlled release polymer matrix and made into tablets ... a a capsule filled with 坆 -like porous polymer matrix. Formulations include solutions, suspensions and emulsions. For example, 177 or H alcohol solution can be used parenterally, or for oral suspensions and emulsions, sweeteners and pacifiers can be added. Preparations in the osmium form may also include solutions for intranasal administration. Suitable aerosol preparations for inhalation may include solids in the form of solutions and powders which may be mixed with a pharmaceutically acceptable carrier such as an inert compressed gas ' such as nitrogen. As for the preparation of suppositories, low-melting point sacrifices, such as fatty acid glycerol, or a mixture of cocoa butter, are first dissolved, and the active ingredient is dispersed uniformly in the towel by mixing or the like. The audible homogeneous mixture is then poured into a suitably sized model 'to allow cooling and thereby solidify. The preparations in solid form are also intended to be converted to preparations in liquid form shortly before use for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be delivered transdermally. Compositions for transdermal delivery can be in the form of 99028.doc • 65- 200536530 in the form of creams, lotions, aerosols and / or emulsions, and can be incorporated into traditional matrices or storage for this purpose in the art Form of transdermal patch-medium. • The compounds of the invention can also be administered orally, intravenously, intranasally or subcutaneously. The compounds of the invention may also include preparations in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate amounts of the active component, for example, an effective amount to achieve the desired purpose. • The amount of the active composition of the present invention in the preparation of unit dose 1 can generally be varied or adjusted from about 丨. 0 mg to about 0.001, preferably from about L0, depending on the particular application. To about 95 mg, more preferably from about 1 mg to about 500 mg, and representatively from about 1 mg to about 250 mg. Depending on the age, sex, weight of the patient and the severity of the condition to be treated, the actual dose used may be changed. Such techniques are well known to those skilled in the art. Normally, a human oral dosage form containing the active ingredient [® or 2 times can be administered daily. The dosage and frequency of administration will be adjusted according to the judgment of the clinician. The recommended daily dose ingestion methods for oral administration can generally range from about 1.0 mg to about mg per day, in single- or divided doses. Some useful terms are described below: Capsules are special containers or seals made of methylcellulose, polyvinyl alcohol, or denatured gelatin or starch to contain or contain the M compound containing the active ingredient It is made by mixing relatively high gel strength bone and osteogelatin. The capsules themselves may contain small amounts of dyes, opacity agents, plasticizers and preservatives. 99028.doc -66-200536530 lozenge-means a compressed or shaped solid dosage form containing an active ingredient plate as appropriate diluent. The bonding agent can be prepared by compressing the mixture or granules obtained by wet granulation, dry granulation, or by "oral gelation." Oral gelation means that the active ingredient is dispersed or dissolved in a hydrophilic semi-solid component and Proper diluent powder for powders-means containing a mixture of active ingredients, which can be suspended in water or fruit juice

Diluent-means a substance that normally constitutes most of the composition or dosage form; suitable diluents include sugars such as lactose, sucrose, mannitol, and xylitol 'native to wheat, corn, rice, and potato starch; and Cellulose, such as microcrystalline cellulose. The amount of dilute in the composition may range from about 10 to about 90% by weight of the total composition, preferably from about 5 to about 60, more preferably from about 30 to about 6 0% by weight, and even more preferably from about 12 to about 60/0. Solubilizer-means a material added to the composition to help it disintegrate (disintegrate) and release a drug. Proper disintegrant powder; "modified starch soluble in cold water" such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, karaya gum, guar gum, tragacanth Gums and agar, cellulose derivatives, > methylcellulose and sodium methylcellulose; microcrystalline cellulose and crosslinked microcrystalline cellulose 'as crosslinked sodium methylcellulose sodium; alginates, Such as: acid and sodium alginate, clay, such as bentonite; and effervescent mixtures. The amount of disintegration " " may range from about 2 to about 15% by weight of the composition. It is from about 4 to about 10 weight 0/0. Binder-means a substance that binds or glues powders " together " and binds them by forming granules 99028.doc -67- 200536530, so during formulation Used as "adhesive". Adhesives have been obtained in diluents or fillers plus cohesive strength. Suitable. Binders include sugars, such as sucrose; starches derived from wheat, corn, rice dima- bell potato; natural gums, such as Alafur gum, gelatin, and tragacanth; derivatives of seaweed, such as alginic acid, Sodium alginate and calcium ammonium alginate; cellulosic materials, such as methylcellulose and m methylcellulose sodium, and propyl methylcellulose; polyethylene ketones; and inorganic substances, such as Mingshi . Binders • The amount in the composition may range from about 2 to about 20% by weight of the composition, preferably from about 3 to about 10% by weight, and more preferably from about ^ to about 6% by weight %. Lubricant-means a substance added to a dosage form to enable tablets, granules, etc. to be released from a mold or prayer mold by reducing friction or grinding after it has been compressed. Suitable lubricants include metal stearates such as magnesium stearate, stearic acid # 5 or potassium stearate; stearic acid; high melting waxes; and water-soluble lubricants such as sodium gaseous, benzene Sodium formate, sodium acetate, sodium oleate, polyethylene glycol and cH. Leucine. Lubricant is added at a very late step before compression because it must appear on the surface of the granules and between them and the part of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.05 to about 2%, and more preferably from about 0.3 to about 15% by weight. 〇 / 〇. Help e d (Glident)-A material that prevents agglomeration and improves the flow characteristics of the particles, making the flow smooth and uniform. Suitable slip agents include stone dioxide or 'moon stone'. The amount of slip agent in the composition can range from about 0.1 to about 5 weight percent of the total composition, and preferably from about 0.5 to about 2 weight. /. . 99028.doc • 68- 200536530 Dosage excipients for the color of a composition or dosage form. This type of π "° grade dye is shaped, and food grade dyes are adsorbed on a suitable agent, such as clay or oxide. The amount of colorant can be changed from a large sum to about 5% by weight, preferably It is from about 〇ι to Daluba bioavailability. It means that compared with the standard or control group, the active drug knife or treatment part is absorbed from the dosage form into the systemic circulation and the degree.

Traditional methods for preparing ingot j are known. Such methods include dry methods, such as direct compression and compression of particles produced by compaction, or wet methods, or other special procedures. Traditional methods of making other forms of administration, such as capsules, suppositories and the like, are also well known. Other specific embodiments of the present invention disclose the use of the compounds or pharmaceutical compositions of the present invention disclosed above for treating diseases such as, for example, hepatitis C and the like. The method includes administering a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention to a patient suffering from such a disease or group of diseases and in need of such treatment. In another embodiment, the compounds of the present invention can be used in a monotherapy mode or in a mixed therapy (e.g., dual-mix, triple-mix, etc.) mode, such as, for example, antiviral and / or immunomodulatory agents, To treat human HCV. Examples of such antiviral and / or immune modulators include Lipa

Waring (available from Schering-Plough Corporation, Madison, New Jersey) and Levovirin (available from ICN Pharmaceuticals, Costa Mesa, California), VP 50406TM (available from Viropharma, Incorporated, Exton, Pennsylvania), ISIS 14803 ™ (available from ISIS 99028.doc • 69 · 200536530

Pharmaceuticals, Carlsbad, California), Heptazyme ™ (available from Ribozyme Pharmaceuticals, Boulder, Colorado), VX 497 ™ (available from Vertex Pharmaceuticals, Cambridge, Massachusetts), Thymosin ™ (available from SciClone Pharmaceuticals San Mateo, California), Maxamine TM (available from Maxim Pharmaceuticals, San Diego, California), mycophenolate mofetil (available from Hoffman-LaRoche, Nutley, New Jersey), Interferons (such as, for example, interferon oc, PEG-interferon alpha conjugates) and their analogs. " PEG-interferon alpha conjugate π is an interferon alpha molecule covalently attached to a PEG molecule. Representative PEG-interferon alpha conjugates include interferon a-2a (RoferonTM, available from Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon a_2a ( For example, sold under the brand name PegasysTM, interferon a-2b (Intron ™, available from Schering-Plough Ugh Corporation), and pegylated interferon a-2b. Form (for example, sold under the trade name PEG-IngelonTM), interferon a-2c (Berofora ™, available from Boehringer Ingelheim, Ingelheim, Germany), or by determining naturally occurring interferon alpha Consensus sequence (InfergenTM, available from Amgen, Thousand Oaks, California). As stated earlier, the invention also includes tautomers, rotamers, Enantiomers and other stereoisomers. Therefore, those skilled in the art know that some of the compounds of the present invention may exist in appropriate isomeric forms. Attempts are made to incorporate such changes within the scope of the invention. Other specific embodiments of the present invention disclose methods for making the compounds 99028.doc -70- 200536530 disclosed herein. The compound can be prepared by several techniques known in the art. An example procedure is outlined in the following reaction meter day. ^ Examples should not be construed as a limitation of the scope of the present invention, which is defined in the scope of application patents in the appendix. Those skilled in the art will know other mechanical paths and similar structures. It should be understood that although the following illustrative examples describe the preparation of several representative compounds of the present invention ', any suitable substitution of both natural and non-natural amino acids will result in the formation of Want compounds. Attempts are made to incorporate such changes within the scope of the invention. Abbreviations The abbreviations used in the description, preparation, and examples are as follows: THF Tetrachloromethane DMF: N, N-dimethylformamidine EtOAc: Acetyl acetate AcOH: Acetate φ HOOBt: 3-Ethyl-1 , 2,)-benzotrihu-4 (3H), EDC1 · 1- (3-monomethylaminopropyl) _3-ethylcarbodiimide hydrochloride NMM: N-methylmorpholine ADDP : 1,1 '-(Azodicarbonyl) dihexahydrolaxidine DEAD: Diethyl azodiweilate' MeOH: Methanol

EtOH: ethanol Et20: diethyl scale DMSO: dimethylsulfite 99028.doc 71 200536530 HOBt: N-hydroxybenzotriazole

PyBrOP: bromo-tri-α bilo σ fixed scale hexafluorocarboxylate DCM: methylene chloride DCC: 1,3-dicyclohexylcarbodiimide TEMPO: 2,2,6,6 · tetrafluorenyl -1-Hydroxyhydroxyl

Phg: phenylglycine

Chg: cyclohexyl glycine

Bn: benzyl

Bzl: benzyl

Et: ethyl

Ph: phenyl iBoc: isobutoxycarbonyl iPr: isopropyl'Bu ^ Bu1: tertiary-butyl Boc: tertiary-butoxycarbonyl Cbz: benzyloxycarbyl Cp: cyclopentylene group Ts: p-fluorene Benzenesulfonyl Me: methyl HATU: 0- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethylphosphonium hexafluorophosphate DMAP ·· 4-N, N-Diamidoaminopyridine BOP: Benzotriazol-1-yl-oxy-tris (diamido) hexafluorophosphate PCC ·· Ingot gas chromate 99028.doc -72- 200536530

KHMDS: Potassium hexamethyldisilazide or potassium bis (trimethylsilylamine) NaHMDS: Potassium hexamethyldisilazide or potassium bis (trimethylsilylamine) LiHMDS: hexamethyldisilazide Lithium Nitride or Bis (trimethylsilyl aminated) Lithium 10% Pd / C: 10% Batch Palladium Charcoal (by weight) TG · Thioglycerin Example Synthesis of Intermediate: Synthesis of Ethyl Ester La:

la According to the procedure described by Monn and Valli (J. Org. Chem. 1994, 59, 2773-2778), ethyl ester 1a was synthesized. Synthesis of Intermediate 1:

Step A

HO

At 0 ° C, add sodium borohydride (924.5 mg) in small portions to the bicyclic mixture in ethanol 99028.doc -73-200536530 f ml), and react for 30 minutes '', and TLC analysis (ethyl acetate / hexane; 1: 1) showed that all starting material had been consumed. The reaction was quenched by the addition of AcOH (3 mL). The mixture was diluted with ethyl acetate, and rinsed with a saturated aqueous solution of oxyxan (50 x liters) and saline (1 x 4 G ml). The organic layer was dehydrated with sulfuric acid, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain a yield of 92 ° /. Product.

Step B

Treated with 1.08 g of 60% NaH suspension at o. At c, a solution of cyclopentanol lb in 130 ml of anhydrous tetrahydrofuran. Remove the cooling bath and stir the kappa color> Valley 30 for the name. Add one * carbon sulfide (16.2¾ liters) 'and teach the reaction for 45 minutes. Methyl iodide (16.8 ml) was then added dropwise, and the mixture was stirred for an additional hour. The remote reaction was quenched by carefully adding a saturated aqueous ammonium chloride solution (30 ml). The mixture was taken with 80 ml of acetam and the layers were separated. The layers were back extracted with ether (2x80 mL). The combined organic layers were washed with water (30 ml) and brine (30 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: hexane to 30% isopropyl S in hexane) to give a xanthate product in 63% yield as a yellow oil.

Step C 99028.doc -74- 200536530

A solution of xanthate 1 (: in 90 ml of toluene was degassed with anhydrous nitrogen. AIBN (150 · 4 mg) and tri-n-butyltin hydride (3.7 ml) were added. The reaction mixture was again Degas' and teach for 1 hour at 95 ° C. TLC analysis (Cg / Hexan, 1: 9) shows that all starting materials have been consumed. Remove all of the starting materials under reduced pressure. Volatile matter, and the residue was dissolved in 250 ml of diethyl ether and rinsed with a saturated aqueous solution of potassium fluoride (2 x 30 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: hexane to 20% ethyl acetate in hexane) to give a product with a yield of 98%.

Step D

At 0 ° C, N-Cbz starting material id (2.5 g) was dissolved in 80 ml of trifluoroacetic acid, followed by 20 ml of dimethylsulfide. The reaction mixture was stirred at 0 Torr for 5 minutes, and the cooling bath was removed. The reaction was stirred for an additional 5 hours. All volatiles were removed under reduced pressure, and the residue was partitioned between dichloromethane (250 ml) and aqueous IN NaOH (50 ml). The liquid layer was counter-stroked with dioxane (2 x 80 ml). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The product was used without further purification (146 g, 97% yield). Step E 99028.doc -75- 200536530

• A solution of Ν-Boc-tertiary-butylleucine in 46 ml of anhydrous dichloromethane and 60 ml of anhydrous dimethylformamide was mixed at 0 ° C with HATU (3.26 g). deal with. Racemic amine le (1.42 g) in dichloromethane (10 ml) was added dropwise, followed by S-methylmorpholine (2.7 ml). The mixture was gradually warmed to room temperature and stirred overnight. All volatiles were removed under reduced pressure (high vacuum) and the residue was dissolved in 350 ml of ether. The combined organic layers were washed with aqueous IN HCL (30 mL), aqueous saturated NaHC03 (30 mL), water (30¾ liters), and brine (30 mL). The organic layer was dehydrated with magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: ether / hexane; 1: 9 to 5: 5) to give a yield of 72 ° /. The diastereomeric products 1 f and 1 g.

Step F

Lithium hydroxide monohydrate (79 mg) was added to a solution of 300 mg of the esterif in 5 ml of a tetrahydrofuran / water / methanol (1: 1: 1) solution. The reaction was stirred at room temperature for about 3 hours until no more starting material was detected by TLC analysis (diethyl ether / hexane; 4: 6). The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and aqueous IN ml) 99028.doc -76- 200536530. The layers were back-extracted with dichloromethane (2x20 mL). The mixed organic layer was dehydrated with sulfuric acid, filtered, and concentrated under reduced pressure. The product was obtained in a yield of 91% as a white solid without further purification. Synthesis of Intermediate 2:

Step A

The stirred solution of ketimine 2a (50 g, 187.1 mmol) in anhydrous THF (400 ml) under N2 was cooled to -78%, and at 1M of K ^ BuO in THF The solution (220 ml, M5 equivalents) was processed. The reaction mixture was warmed to 0 ° C, stirred for 1 hour, and then treated with bromomethylcyclohexane (28 mL, 249¾ moles). The reaction mixture was stirred at room temperature for 48 hours and concentrated in vacuo. The residue was dissolved in Et20 (300 ml) and treated with aqueous HC1 (2M, 300 ml). The resulting solution was stirred at room temperature for 5 hours and extracted with Et20 (1 liter). The layer was basified with NaOH (50% aqueous solution), basified to PHM2-U, and extracted with CH2C12 (3 x 300 mL). The combined organic layers were dehydrated (MgS04), filtered and concentrated to give pure amine (2.18 g) as a colorless oil.

Step B 99028.doc -77- 200536530

2b 2c

A solution of amine 2b (18 g, 105.2 mmol) in CH2C12 (350 ml) was treated with di-tertiary-butyl dicarboxylic acid (23 g, 105.4 mmol) and placed in a chamber. Stir at temperature for 12 hours. After the reaction was completed (TLC), the reaction mixture was concentrated in vacuo, and the residue was dissolved in THF / H20 (200 ml, 1: 1) and treated with LiOH.H20 (6.5 g, 158.5 mmol), Then stir at room temperature for 3 hours. The reaction mixture was concentrated and the sensible liquid layer was extracted with Et20. The liquid layer was acidified to pH ~ 1-2 with concentrated HC1 and extracted with CH2C12. The combined organic layers were dehydrated (MgS04), filtered and concentrated in vacuo to give 2c as a colorless, viscous oil, which was used in the next step without any further purification.

Step C

BocHN

Treated with BOP reagent (41.1 g, 93 mmol), N-methylmorpholine (27 ml), N, 0-dimethylhydroxylamine hydrochloride (9.07 g, 93 mmol) in CH2C12 (250 ml) of a solution of the acid 2c (15.0 g, 62 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with 1N aqueous HC1 (250 ml), the layers were separated, and the liquid layer was extracted with CH2C12 (3 x 300 ml). The combined organic layers were dehydrated (MgSCU), filtered and concentrated in vacuo, and purified by layer chromatography (Si02, EtOAc / Hex 2: 3) to give amines as a colorless solid 99028.doc -78- 200536530

2d (15.0 g). Step D 〇 〇 BocHN ^^ U ^ 〇Me BocHN ^ A X ^ 2d 2θ

A solution of amidine 2d (15 g, 52.1 mmol) in anhydrous THF (200 mL) was treated dropwise with a solution of LiAlH4 (1M, 93 mL, 93 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, and carefully quenched with a KHS04 solution (10% aqueous) at 0 ° C, and then stirred for 0.5 hours. The reaction mixture was diluted with aqueous HC1 (1M, 150 ml) and extracted with CH2C12 (3 x 200 ml). The mixed organic layer was washed with aqueous HC1 (1M), saturated NaHC03, brine, and dehydrated (MgS04). The mixture was filtered and concentrated in vacuo to give 2e (14 g) as a sticky colorless oil.

Step E

2§ 2f Treat with CH1Cl2 (50ml) with £ 1: 3 > ^ (10.73 耄 liter, 74.4 耄 mole) and propane | isocyanide (10.86% g '127.57¾mol). A solution of acid 2e (14 g, 61.6 mmol) was stirred at room temperature for 24 hours. The reaction compound was concentrated in vacuo and diluted with aqueous HC1 (1M, 200 ml), and extracted into CH2C12 (3 x 200 ml). The mixed organic layer was washed with 40, brine, dehydrated (MgS04), filtered, concentrated in vacuo and purified by chromatography 99028.doc -79- 200536530 (Si02, EtOAc / Hex 1: 4), 2f (10.3 g) was produced as a colorless liquid.

Step F

BocHN

2f

HC1 saturated methanol * (prepared by bubbling HC1 gas in CH3OH (700 ml) at 0 ° C) was treated with cyanohydrin 2f and heated to reflux for 24 hours. The reaction was concentrated in vacuo to give 2 g, which was used directly in the next step without purification. * Alternatively, 6M HC1 prepared by adding AcCl to anhydrous methanol can also be used.

Step G

OH BocHN

2h

A solution of 2 g of the amine hydrochloride in CH2C12 (200 mL) was treated with Et3N (45.0 mL, 315 mmol) and Boc20 (45.7 g, 209 mmol) at -78 ° C. The reaction mixture was then stirred at room temperature overnight, diluted with HC1 (2M, 200 mL), and then extracted into CH2C12. The combined organic layers were dehydrated (MgS04), filtered, concentrated in vacuo, and purified by chromatography (EtOAc / Hex 1: 4) to give the alkyl ester 2h. Step Η 99028.doc -SO- 200536530

OH BocHN

2h

OH BocHN

21 Treat a solution of the methyl ester in THF / H20 (1: 1) for 2 h (3 g, 10.5 mmol) with Li0H.H20 (645 mg, 15.75 mmol) and stir at room temperature for 2 hours . The reaction mixture was acidified with aqueous HC1 (1M, 15 ml) and concentrated in vacuo. The residue was dehydrated in vacuo to give 2i in quantitative yield.

Step I

OH OH

2 »2i with ^^ 114 € 1 (2.94 g, 55.5 mmol), ugly 0: 1 (3.15 g, 16.5 mmol), HOOBt (2.69 g, 16.5 mmol) and NMM (4.4 G, 44 mmol) was treated with a solution of the acid 2i (from above) in CH2C12 (50 ml) and DMF (25 ml). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed under vacuum and the residue was diluted with aqueous HC1 (250 ml) and extracted with CH2C12. The mixed organic layer was washed with aqueous saturated NaHC03, dehydrated (MgS04), filtered, and concentrated in vacuo to obtain 2j, and it was used as such in the following steps. (Alternatively, 2j (4.5 g, 17.7 mmol) and water-containing H2O2 (10 ml), 1 ^ 0 ± 1120 (820 mg, 20.8 millimolars) for 0.5 hours to directly obtain 2j).

Step J 99028.doc -81-200536530

OH BocHN

NH2

OH CIH3N

NH2 2i 2 The 2j solution obtained in the previous step was dissolved in 4N HC1 in No. 2 roast and stirred at room temperature for 2 hours. The reaction mixture 'was concentrated in vacuo to give intermediate 2 as a solid, which was used directly without further purification. Synthesis of Intermediate 3:

Step A

3

L-Third · leucine (1 equivalent, 10 g) was slowly added to a suspension of lithium aluminum hydride (150 mmol, 1 M solution in THF). The reaction mixture was refluxed for 6 hours. The mixture was cooled to zero. And quenched by adding 10 ml of aqueous 10% NaOH and 10 ml of water. The mixture was stirred at room temperature for 1 minute, then treated with di-third-butyl dicarbonate (11 equivalents, 1822 g), and the mixture was stirred at 60 C overnight. The reaction mixture was filtered through magnesium sulfate. The filtrate was concentrated and the residue was chromatographed on silica to give the product 3b in 62% yield.

Step B 99028.doc -82-200536530

Add triphenylphosphine (3 equivalents) and alcohol 3b (1 equivalent) to 50 mL of anhydrous THF

In a solution of phthalimide (Lol). The mixture was cooled in an ice-water bath, and diisopropyl azodicarboxylate (2.5 equivalents) was added dropwise. The resulting mixture was stirred at 0 ° C for 10 minutes and warmed to room temperature, and then simmered for about 2.5 hours until no more onset was detected by TLC (ethyl acetate / hexane; 3: 7). So far. The mixture was concentrated under reduced pressure. The residue was resuspended in 80 ml of digas methane. Filter off the solid. The filtrate was concentrated to half its volume and hexane (30 ml) was added. Filter off the solid. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (gradient: ethyl acetate / hexane, 1: 9 to 4: 6) to give the product 3c.

Step C

N-Boc protected amine 30 (1.4 g) was dissolved in 20 ml of 4M HC1 solution in dioxane. The mixture was stirred for about 2 hours. Remove everything under vacuum

Some volatiles. No further purification was required for product 3 (1. Step D

Under 0C, treat amine hydrochloride in 99028.doc -83-200536530 with 20 ml of dichloromethane and 20 ml of saturated NaHC03 aqueous solution with phosgene (10 ml, 15% solution in toluene) 3d ( 1.14 g) of the mixture and stirred for 2 hours. The reaction mixture was diluted with 100 ml of dichloromethane and washed with 30 ml of a cold saturated aqueous NaHCO3 solution. The organic layer was dehydrated with magnesium sulfate, filtered, and further diluted with 10 ml of toluene. The mixture was concentrated and product 3 was kept as a 0.2M solution in toluene. Synthesis of Intermediate 4:

Step A

4a

At 0 ° C, cyclopropylmagnesium bromide (4 equivalents, 7.68 mmol) was added to amidine 4a (0-5 grams, 1 equivalent) in THF. After the reaction was warmed to room temperature for a maximum of 15 minutes, the reaction was stirred at room temperature for 5 hours, and then the flame was added by adding IN HC1. The reaction was diluted with EtOAc and washed with brine. The organic layer was dried over MgS04 and purified by column chromatography with 10% EtOAc in hexane to obtain 0.2 g of the product. The output was 43.1%.

Step B

4M HC1 (in dioxane) was added to the N_Boc protected amine 4b (02 g) 99028.doc -84-200536530. The reaction was stirred at room temperature for 50 minutes, and TLC indicated that the reaction was complete. The mixture was concentrated to dryness to give 0.162 g of product 4c.

Step C

At 0 ° C, 4c was added to phosgene (2 equivalents, 1.65 mmol), NaHC03 (5 ml saturated aqueous solution) in CH2C12. The mixture was stirred at room temperature for 2.5 hours. Separated by funnel. The organic layer was dried over Na 2 SO 4 (anhydrous). It was concentrated to half the volume using a cooling bath. Dilute to 10 ml to obtain the desired isocyanate 4 as a 0.083 m solution in dichloromethane. Synthesis of Intermediate 5:

Step A

Under nitrogen pressure at -78 ° C, KHMDS (200 ml of a 0.5 M solution in toluene) was added dropwise to ethyl hexane carboxylate 5a (l 1.1 g, 78 mmol) in no ml). Mol) in a stirred solution. When the addition was complete, the reaction was maintained at this temperature for an additional 0.5 hours, and then benzyl amidino ether (18.6 ml, 134 mmol) was added. Allow the reaction to warm to room temperature 99028.doc -85- 200536530 and add water (100 ml). Aqueous treatment provided the residue, which was purified by Shixi gel column chromatography using EtoAC; hexane (1:10) as the eluent to obtain the desired, impure intermediate ether (14.98 g) as colorless Of oil.

A black suspension of 10% Pd / c (0.4) in MeOH (80 mL) and the aforementioned crude ether (4.1 g) was exposed to nitrogen pressure (balloon) at room temperature. The reaction was filtered through a celite pad and the solids were rinsed thoroughly with methanol. The mixed filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using Et0Ac; hexane (1: 5) to obtain a primary alcohol (5b; 0.62 g) as a colorless oil. .

Step B

To a stirred solution of primary alcohol (5b; 0.62 g) was added trioxane (0.53 ml) under a nitrogen pressure of 0 ° C, followed by triethylamine (0.75 ml). The resulting mixture was stirred at this temperature for 0.5 hours. The reaction mixture was extracted into EtOAc and washed with 1M HC1, saturated aqueous NaHC03, water, dehydrated (MgSCU) and concentrated. A yellow oily residue was obtained (5G; 0.74 g), which was used directly in the next step without purification. Step C

Dimethylamidamine (20 ml; anhydrous; Aldrich) was added to sodium hydride 99028.doc -86 · 200536530

(0.56 g, Aldrich), and tertiary-butyl mercaptan was added to the suspension while cooling in an ice bath under nitrogen pressure. Once the addition was complete, the mesylate (5c; prepared from 2.00 g of alcohol 5b as above) was added and the resulting mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and water, and the organic phase was separated and dehydrated (MgS04). Column chromatography on silica gel using EtOAc-hexane (2:98) provided methyl ester-sulfide (5d; 175 g). EtOAc was added to the liquid phase, and 10% aqueous HC1 was added until the aqueous layer pH = 1. The organic layer was separated, washed with water, dehydrated, and concentrated under reduced pressure to obtain the sulfide-carboxylic acid (5e; 0.747 g) as a white solid.

Step D

5e 5f

A bisulfate preparation (1 8.00 g; Aldrich) was added to the sulfide (5e; 2.287 g) in methanol (75 ml), and the resulting white suspension was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the white solid was partitioned between EtOAc and water. The organic phase was separated, dehydrated and concentrated to provide sulfone (5f; 2.52 g; containing some solvents).

Step E

A solution of the acid 5f (1.6i g) in 50 ml of toluene was treated with DPPA (1 equivalent, 1.33 ml, dl.270) and triethylamine (1 equivalent, 0.85 ml, d 0.726). 99028.doc -87- 200536530 fluid. The mixture was heated to loot: 2 hours. The reaction mixture was diluted with aqueous saturated NaHC03 and extracted with two gaseous methane (2 × 100 mL). The mixed organic layer was washed with water-saturated NaHC03 and brine. The organic layer was dehydrated with MgS04, filtered, and concentrated under reduced pressure until about 20 ml of solvent remained. The solution of product 5 was adjusted to a concentration of 0.2 M isocyanate using toluene. Synthesis of intermediate 6:

Step A

6 〇

Hydrazine (0.9 mL, 28.68 mmol, 1.4 equivalents) was added to a solution of o-phthalimidine 3c (7 g) in 100 mL of MeOH, and the mixture was refluxed (under N2 Bottom) 6 hours. TLC showed some starting material, more hydrazine (0.45 ml) was added, and stirring was continued at room temperature overnight. A white precipitate formed. The solid was filtered off and the filtrate was concentrated to give the product 6a (4.48 g) as a white solid.

6b

Step B 99028.doc -88- 200536530 The solution of the amine 6a (216 g, 10 mmol) in 100 ml of digas methane was cooled to (TC) and treated with triethylamine (2 equivalents, 28 ml). Methanesulfonium chloride (1.2 equivalents, 0.93 ml) was added dropwise. The heterogeneous mixture was stirred overnight (temperature 0 to 25. 0. The solid was filtered off, and a saturated aqueous solution of rubidium chloride (100 ¾ liter) and brine ( 100 ml). The organic layer was dehydrated with magnesium sulfate, filtered and concentrated. The residue was dissolved in a small amount of methane / ethyl acetate (about 10 ml) and the insoluble white solid was filtered off. On silica gel By tube

The filtrate was purified by column chromatography to give the product 6b (2.7 g) as a thick semi-solid. Step C

A solution of sulfamethoxamine 6b (2_2 g, 7.5 mmol) in 50 ml of anhydrous DMF was cooled to 0 ° C and treated with a carbonic acid planer (3 equivalents, 7.34 g). Methyl iodide (5 equivalents, 2.34 ml) was added dropwise, and the mixture was stirred for 45 minutes. The cooling bath 'was removed and the mixture was stirred for another 4 hours. The reaction was quenched by the addition of a saturated aqueous solution of gasified ammonium (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (200 ml) and brine (200 ml) and dried over sodium sulfate. The organic layer was filtered and concentrated. The residue was layered on Shi Xijiao to obtain the product 6c (2-16 g).

N-Boc protected amine 6c (2.1 g, 6.82 mmol) was dissolved at room temperature in 99028.doc -89- 200536530 in 20 ml of 4M HC1 in dioxane. The reaction mixture was stirred for 1 hour and then all volatiles were removed under reduced pressure to give the product in quantitative yield for 6 days.

Step E

A mixture of amine hydrochloride 6d in dichloromethane and saturated aqueous NaHC03 solution was treated with phosgene (15% solution in toluene) at 0 ° C and allowed to stir for 2 hours. The reaction mixture was diluted with digas methane and washed with cold saturated aqueous NaHC03 solution. The organic layer was dehydrated with magnesium sulfate, transitioned and further diluted with transcript. The mixture was concentrated and product 6 was adjusted to maintain a 0.2 M solution in toluene. Synthesis of Intermediate 7:

According to the description of isocyanate 6, isocyanate 7 was prepared. In the sulfonamide synthesis step, 2-thiophenesulfonium gas is used instead of methanesulfonyl chloride. Synthesis of Intermediate 8:

99028.doc -90- 200536530

Step A

G of 'Aldnch) was added to a solution of 4-pentyne-1 -ol, 8a (4.15 g, Aldrich)' and the resulting mixture was stirred for 45 minutes, after which (third-butoxycarbonylmethylene) triphenyl was added Orthophosphine (26.75 g; Aldrich). The resulting dark reaction was stirred overnight 'and diluted with ethyl acetate, washed with aqueous sodium sulfite, saturated aqueous sodium hydrogen carbonate solution, water, brine, and dehydrated. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography using 1% ethyl acetate in the hospital as the eluent to obtain the desired compound.

8b (3.92 g). Some impure dissolution was also obtained, but it was ignored at this time. Step B

Use dilute 8b (1.9 g) in n-propanol (20 ml; Aldrich), benzyl carbamate (4.95 g; Aldrich) in n-propanol (40 ml), and water (79 ml) NaOH, tert-butyl hypochlorite (3.7 ml), (DHQ) 2PHAL (0.423 g; Aldrich) in n-propanol (37.5 ml) and potassium oxalate: anhydrate (0.1544 g; Aldrich ), And the procedures set out in Angew. Chem. Int. Ed. Engl (l998), 35, (23/24), pages 28 13-7, to obtain the crude product, which was purified by silica gel column chromatography, Using EtOAc: hexane (1: 5), the desired amino alcohol 8c (1.37 g, 37%) was obtained as a white solid. 99028.doc -91-200536530 step c

4M HC1 (20 ml; Aldrich) in diuridine was added to the ester, and the resulting mixture was allowed to stand at room temperature overnight. The volatiles were removed under reduced pressure to give 8d (0.621 g) of acid as a white solid.

Step D

Add 600 mM reagent (3.65 g; 3 811 ^) to a solution of carboxylic acid 8 (1 (2.00 g) in dichloromethane (20 ml) and acrylamine (0.616 ml) at room temperature, then add three Ethylamine (3.45 ml), and the resulting mixture was stirred overnight. The reaction mixture was partitioned between EtOAc and 10% aqueous HC1. The organic phase was separated, washed with saturated aqueous sodium hydrogen carbonate solution, water, and dehydrated (magnesium sulfate) The crude reaction product was purified by silica gel column chromatography using (EtOAc: hexane; 70:30) as the eluent to provide the desired amidine 8e (1.73 g) as a viscous yellow oil 0

Step E

Cbz

8e

8 Stir a solution of N-Cbz amine 8e (85.8 mg) in 5 ml of a 4: 1 mixture of trifluoroacetic acid / dioxine at room temperature for approximately 3 hours. Move 99028.doc -92- 200536530 under reduced pressure and remove all volatiles. The product 8 was placed under high vacuum for approximately 3 hours and used directly without further purification. Synthesis of Intermediate 9: Step 1

Add zinc powder (21 g, 320 mmol), zirconecene dichloride (14.04 g, 48 mmol) to la (13.24 g, 40 mmol) in THF (200 ml), Prepared as described in Monn and Valli, J. Org. Chem., 1994, 59, 2773-2778), and finally dibromomethane (6.18 ml, 44 mmol) was added dropwise. The reaction mixture was heated to reflux for 5 hours. It was then cooled to room temperature and then cooled to 0 ° C using an ice bath. Add water dropwise (Caution: exothermic) until gas evolution ceases. Diethyl ether (400 ml) was added and the mixture was filtered through a celite pad. Rinse the filter cake with ether (200 ml), and rinse the combined filtrate with water (2x500 ml), aqueous 1N HC1 (500 ml), water (500 ml), brine (500 ml), dehydrate (Na2S04), and filter And concentrated. The crude material was purified by flash chromatography using 10/90 to 20/80 EtOAc / hexane to give 6.82 g of 9a as a pale yellow oil. Step 2

99028.doc -93-200536530 Diethylzinc (1M in heptane, 73 ml, 73 mmol) was added to two gaseous methane (000 ml) under a nitrogen pressure of 0 ° C. Difluoroacetic acid (5.6 ml, 73 mmol) was added dropwise over 30 minutes. Maintain the temperature for an additional 15-20 minutes. Then diiodomethane · 9 ml, nanomolar was added dropwise over 20 minutes, and the temperature was maintained for an additional 15-20 minutes. Finally, a solution of 9a (4-8 g, 14.6 mmol) in dichloromethane (20 ml) was added dropwise. The reaction mixture was warmed to room temperature over 16 hours. The reaction mixture was then cooled to 0 C and quenched by slowly adding a saturated ammonium chloride solution (200 ml). The layers were separated and extracted with dichloromethane (125 ml). The mixed organic layers were washed with saturated sodium bicarbonate and brine, dried (Na2SO4), filtered and filtered. Purification of the crude material by flash chromatography, using 15/85

EtOAc / hexane to give 2.89 g of 9b. Step 3

Add 4M HC1 (2 ml) in 25 ° C and a 10% batch of palladium charcoal in a catalytic amount to 9b (2.41 g, 7.03 mmol) in ethanol (100 ml). The mixture was hydrogenated using a balloon filled with hydrogen at room temperature for 5 hours. At this point additional portions of catalyst were added and the mixture was hydrogenated over 16 hours. The reaction was stopped, filtered through a pad of diatomaceous earth, washed with ethanol, and the filtrate was concentrated to obtain 74 g of 9 which can be used directly without further purification. Synthesis of intermediate 10 99028.doc -94- 200536530

Cbz〇 9b

Using the hydrogenation procedure described above (step 3), platinum 9 (W) was used in place of 10% of the batch wood to convert Compound 9b into the desired material 10. synthesis:

Step A

A solution of 4,4-dimethylglutariminium Ua (1.5 equivalents, 4.86 g, Aldrich) in 200 ml of anhydrous THF was cooled to 0 ° C, and triphenylphosphine (3-when 1 , I8.07 g) and S-Boc-tertiary-butyl glycinol (glycinol) 11b (5 g, Aldrich). Diisopropyl azodichlorate (2.5 equivalents, 11.3 ml, dl.027) was added dropwise at 0 ° C. The resulting solution was stirred at 0 ° C. After 10 minutes, the mixture became a slurry and stirring was continued to 25 overnight. (:). The mixture was concentrated under reduced pressure, and the residue was dissolved in 80 ml of ether. Hexane (100 ml) was added and the precipitated solid was filtered off. The filtrate was concentrated to half its volume, and hexane (100 ml) was added again. Filter off the solid. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate / hexane; 2: 8) —to give the product Uc (40 g; 51%) as a white solid. 99028.doc -95- 200536530

Step B

N-Boc protected amine 11c (3 g) was dissolved in 50 ml of a 4M HC1 solution in dioxane. The reaction mixture was stirred for about 1 hour until it was judged by TLC analysis (ethyl acetate / hexane; 2: 8) that the starting material had been consumed as

stop. All volatiles were removed under reduced pressure to give the product 11d (2.4 g, 98%) as a white solid.

Step C

A solution of the amine hydrochloride lld (1.0 g) in 40 ml of dichloromethane was treated with 40 ml of a saturated aqueous sodium bicarbonate solution, and vigorously searched at 0 ° C for 10 minutes. Stop stirring and allow the layers to separate. Phosgene (10 ml of a 200/0 solution in toluene) was added in portions to the organic layer (lower layer) via a needle. Immediately after the addition, the mixture was stirred vigorously at 0 ° C for 10 minutes, and further stirred at room temperature for 2.5 hours. The mixture was diluted with 100 ml of digas methane and the layers were separated. The organic layer was washed with 30 ml of a cold saturated aqueous sodium hydrogen carbonate solution, and dried over magnesium sulfate. The organic layer was filtered, and the filtrate was diluted with 50 ml of toluene. The resulting solution was concentrated and the product 11le was kept as a 0.241M solution.

Step D 99028.doc -96- 200536530

A solution of acid 1 (2.19 g) in 40 ml of anhydrous DHF was cooled to zero. And treated with cesium carbonate (1.2 equivalents, 1.22 g), followed by the addition of benzyl bromide (2. 2 equivalents, 0.85 ml, d 1.438). The reaction mixture was stirred for 24 hours (temperature: 0 to 25 ° C). The mixture was diluted with ethyl acetate (350 ml) and water

(3x50 0 liters) Flush. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a stone gum (gradient: hexane vs. ethyl acetate / hexane 25:75) to give the product 1 if (2.1 g; 77%) as a clear oil.

Step E

N-Boc protected amine 11f (2.1 g) was dissolved in 50 ml of a 4M HC1 solution in diuridine. The resulting solution was stirred at room temperature until it was judged by tLC analysis (ethyl acetate / hexane; 25:75) that all starting materials had been consumed. After 1 hour, all volatiles were removed under reduced pressure to give 11 g (1.8 g; 98%) of the product as a white solid.

Step F

Treated with N-methylmorphine (2.5 equivalents, 0.7 ml, d 0.920) at 0 ° C 99028.doc -97- 200536530

A solution of 11 g of amine hydrochloride in 10 ml of dry dichloromethane. The resulting solution was filtered off for 5 minutes, and then isocyanate lle (1.3 equivalents, 136 ml of a 0.22 14M solution in toluene) was added. The reaction mixture was stirred for 5 minutes and the cooling bath was removed. The mixture was further stirred for 2 hours. The mixture was partitioned between digas methane (200 ml) and aqueous 1M HC1 (50 ml). The layers were separated and the organic layer was washed with a saturated aqueous sodium bicarbonate solution (50 ml). The organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on a stone gum (gradient: acetone / hexane; 5:95 to 35:65) to give the product 11h (1.33 g; 84%) as a white solid.

Step G

Dissolve benzyl ester llh (1.3 g) in 30 ml of ethyl acetate and add 20%

Treated with palladium hydroxide charcoal (0.1 mole%; 145 mg). The heterogeneous mixture was hydrogenated at 50 crushes per square inch for 2 hours. The mixture was diluted with 200 ml of dichloromethane and filtered through short-circuited diatomaceous earth. The filtrate was concentrated under reduced pressure to give the product 11 (1.1 g; 98%) as a white solid. synthesis·

12

Step A

12b 99028.doc -98- 200536530 in order, N, 0-dimethyl via amine hydrochloride (ΐι equivalent, ⑽mg), BOP reagent (1.1 equivalent, 4.47 g), and methyl morpholine (η equivalent) (N ml, d.920) was treated with 100 ml of anhydrous dichloromethane and 12 ml (2 g) of acid in feet. The mixture was heated to scratch overnight. The reaction mixture was concentrated to half its volume and diluted with 400 ml of ethyl acetate. The organic layer was washed with water (80 ml), aqueous 1 MΗα⑽ ml), a saturated sodium chloride carbonate aqueous solution (80 ml), and brine (80 ml). The organic layer was dried over magnesium sulfate and filtered 'and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexane; 5:95 to 3: 7) to give the product 12b as a clear oil.

Step B

A solution of amidoamine 121) (2.2 g) in 100 ml of anhydrous THF was cooled to 0 ° C. A solution of lithium aluminum hydride (13 equivalents) was added dropwise. After 5 minutes the cold section was removed 'and the mixture was allowed to reach room temperature. TLC analysis (ethyl acetate / hexane ' 2: 8) showed that all starting materials had been consumed. By adding a few drops of water-saturated sodium bisulfate, carefully quench the excess LAH. The mixture was diluted with 200 ml of ethyl acetate, and aqueous saturated sodium bisulfate was added in small portions until a white solid was precipitated. The mixture was filtered through diatomaceous earth, and the filtrate was washed with 50¾ liters of brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient · ethyl acetate / hexane; 5:95 to 4: 6) 'to give the aldehyde product 12c as a colorless oil.

Step C 99028.doc -99- 200536530

Isonitrile (1.1 equivalents, 680 mg) and acetic acid (2 equivalents, 102 mL, d

1.0 149) A solution of aldehyde 12c (18 g) in 100 ml of dry dichloromethane was treated. The mixture was stirred overnight. All volatiles were removed under vacuum, and the residue was chromatographed on a slab gel (gradient: ethyl acetate / hexane; 2: 8 to 6: 4) to give the product 12d as a white solid.

Step D

V

A solution of the acetate 12d (16 g) in 60 ml of a 1: 1: 1 mixture of THF / Me0H / water was treated with benzyl hydroxide, and stirred for approximately until analyzed by TLC (ethyl acetate / Hexane; 丨: 丨) It is determined that all the starting materials have been consumed. The volatiles were removed in a rotary evaporator and the residue was diluted with dioxane (150 ml). The layers were separated, the layer was diluted with 30 ml of a saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (3 x 80 ml). The mixed organic layer was dried over magnesium sulfate, filtered, and concentrated to give the product 12e as a white solid.

OH ΗΟΙΗ2Ν ^ Λ ^ N 12 1 N-Boc-protected amine i2e (1.5 g) was dissolved in 20 ml of diurinane 99028.doc -100- 200536530 4MHm. The reaction mixture was stirred for hours until all the starting material had been consumed. All volatiles were removed under vacuum to give the product 12 as a white solid. synthesis:

13 Prepare amine hydrochloride according to the synthetic route described for preparing amine hydrochloride 丨 2

13. Commercially available N_Boc-D, L-norvaline acid was used as the starting material, and allyl isocyanide was used instead of cyclopropyl isocyanide to form the corresponding dilute propyl fermented amine. synthesis:

OH

Preparation of amine hydrochloride according to the synthetic route described for the preparation of amine hydrochloride 12

14. N-B0C-D, L-norleucine was used as the starting material, and allyl isocyanide was used instead of cyclopropyl isocyanide to form the corresponding allyl amine. synthesis:

15 According to the synthetic route described for the preparation of amine hydrochloride 12, amine hydrochloride 15 is prepared. Using commercially available N-Boc-/?-Cyclopropyl-D, L · alanine as starting materials, and using allyl isocyanide instead of cyclopropyl isocyanide, the phase 99028.doc 101-200536530 was formed

Corresponding dilute propyl amine. Synthesis of Inhibitors. Preparation Example A

Stir in 5 ml of anhydrous dichloromethane at 0 ° C.

And 5 ml of anhydrous DMF

A solution of acid 1 (255 mg) and treated with HATU (368 mg). Wolves hydrochloride 2 (201 g) was added 'followed by N-methylmorphine (0.42 ml). The reaction was gradually warmed to room temperature and stirred overnight. All volatiles were removed under vacuum and the residue was dissolved in 100 ml of ethyl acetate. The organic layer was washed with aqueous IN HC1 (15 ml), saturated aqueous NaHC03 (15 ml), water (15 ml), brine (15 ml), covered with MgS04, dehydrated, filtered and concentrated under reduced pressure. The desired product A1 is obtained. No further purification of the product was required. Step 2 99028.doc -102- 200536530

Μ Α2 was treated with EDC1 (1.3 g) and dichloroacetic acid (0.42 ml, d 1.563) at 20

A ml (360 mg) solution of A1 in a 1: 1 mixture of toluene / DMSO. The reaction mixture was stirred at room temperature for about 3 hours. The reaction mixture was diluted with methane (100 mL) and washed with aqueous saturated NaHC03 (15 mL), 1NHC1 (15 mL) and brine (15 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexane; 2: 8 to 5: 5) to give the product A2 in 84% yield. Step 3

N-Boc protected amine A2 was treated with 10 ml of acetic acid. Stir the resulting solution 2

】 4. Remove all volatiles under reduced pressure. No further purification of product A) is required. Step 4

N-fluorenylmorpholine (0.037 ml, do0902) was added to a solution of the amine salt A3 in methane anhydrous monochlorine 99028.doc -103- 200536530 methane. The resulting solution was cooled in an ice-water bath, and a solution of isocyanate in toluene (2.5 ml of a 0.13 5 ^ 4 solution) was slowly added. Stir the mixture for 2 hours (temperature 0 to 25 °. Dilute the reaction mixture with 60 ml of mono-gas methylbenzene and rinse with 15 μl of water containing 1 v c 1. Back extract with dichloromethane (2 x 20 ml) Layer. The mixed organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on stone gum (gradient: acetone / hexane; 1: 9 to 6: 4) to give a white color. Solid

Product A (15 mg), yield 20%. Calculated HRMS (FAB) C37H53N607 [M + H] 693.3976; experimental value 693.3987.

Preparation Example B

step 1

N-methylmorpholine (0.037 mL, d 0.920) was added to a solution of the amine salt A3 in 1 mL of anhydrous dioxane. The resulting solution was cooled in an ice-water bath, and a solution of isocyanate 4 in toluene (0.64 ml of 99028.doc • 104-200536530 0.538M solution) was slowly added. The mixture was stirred for 2 hours (temperature 0 to 25 ° C). The reaction mixture was diluted with 60 milliliters of dioxane and washed with 15 mL of aqueous iN HC1. The layers were back extracted with dichloromethane (2x20 ml). The mixed organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on Shi Xijiao (gradient: acetone / hexane; 1: 9 to 6: 4) to obtain the product B (14.6 mg) as a white solid with a yield of 22%. HRMS (FAB) Calculated value for C31H5 () N50 [M + H] 588.3761; experimental value 588.3757.

Preparation Example C

step 1

N-methylmorpholine (0.037 ml, d 0.920) was added to a solution of the amine salt A3 in 1 ml of anhydrous dioxane. The resulting solution was cooled in an ice-water bath, and a solution of isocyanate 5 in toluene (1.4 ml of 99028.doc-105-200536530 0.250M solution) was slowly added. The mixture was stirred for 2 hours (temperature 0 to 25 ° C. The reaction mixture was diluted with 60 ml of monogas and washed with 15 ml of aqueous 1N HC1. The layers were back extracted with dichloromethane (2 x 20 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexane; 1: 9 to 6: 4) to give the product C (white 9.7 mg), yield 13%. Calculated value of hRMS (FAB) C34H58N5007S [M + H] 680.4057; experimental value 680.4066.

Preparation Example D

step 1

N-methylmorphine (0.037 ml, branch 92) was added to a solution of the amine A3 in methylene chloride dimethylbenzene. The resulting solution Γ was cooled in an ice-water bath, and a solution of isocyanate 6 in toluene (1.340M solution) was slowly added. Stir the mixture for 2 hours (temperature 0 to 25. 0 to 60 99028.doc ~ 106-200536530

The reaction mixture was diluted with liters of dichloromethane and rinsed with 5 ml of aqueous 1N HC1. The layers were back-extracted with dichloromethane (2x20 mL). The mixed organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (gradient: acetone / hexane; 1: 9 to 6: 4) to give the product D (23 mg) as a white solid with a yield of 32%. hrms (fab) C3iH55N6〇7S • 3870 ° Preparation Example Ε

[M + H] calculated value655 · 3853; experimental value 655

step 1

N-methylmorpholine (0-037 ml, d 0.92) was added to a solution of the amine A3 in 1 ml of anhydrous dichloromethane. The resulting solution was cooled in an ice-water bath, and a solution of isocyanate 7 in toluene (4 ml of a 0.250 M solution) was added thereto. The mixture was stirred for 2 hours (temperature 0 to 25.0. The reaction mixture was diluted with 60 ml of dichloromethane and rinsed with 15 ml of aqueous 1N. The layer was back-extracted with dichloromethane (2 x 20 ml). Mixed Organic 99028.doc -107- 200536530

The layer was filtered through dehydration with osmium sulfate, and concentrated under reduced pressure. The residue was chromatographed on Shixi gum (gradient: acetone / hexane; 1: 9 to 6: 4) to give the product E (11.5 mg) as a white solid with a yield of 14%. HRMS (FAB) (: 34Η55N60782 [M + Η] Calculated 723.3574; Experimental 723.3568. Preparation Example F Step 1

F

ΌΗ Ο person e f3c ’, o η3ν

II

II

El was stirred at 0 ° C in a solution of 1 ml of anhydrous digas methane and 10 ml of anhydrous acid 17 (280 mg) and treated with HATU (1.4 equivalents, 405 mg). Amine salt 8 in methane (1.3 equivalents, 569 mg). Then N-fluorenylmorpholine (4 equivalents, 0.33 ml, d 0.920) was added. The reaction mixture was stirred for 48 hours at. Remove all volatiles under vacuum and dissolve the residue in 200 ml of ethyl acetate. Water (30 ml), human water IN HC1 (30 ml), aqueous saturated sodium bicarbonate (3 〇mL) and hoof water (30mL). The organic layer was washed. The organic layer was dehydrated with magnesium sulfate, processed and concentrated under reduced pressure. The product F1 was used directly without further purification step 2 ° 99028.doc- 108200536530

A solution of mesitylaminol (415 g) in 20 ml of anhydrous spargas was treated with Dess-Martin quake (3 eq, 966 mg). Disturb at room temperature

The reaction mixture was 45 minutes. The mixture was treated with a 1 M aqueous sodium thiosulfate solution (15 ml) and a saturated aqueous sodium bicarbonate solution (15 ml) and stirred for 15 minutes. The mixture was extracted with dichloromethane (3x50 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexane; 1: 9 to 4: 6) to give the product F2 as a colorless oil. Step 3

N-Boc-protected amine F2 (155 mg) was dissolved in 5 ml of 4MHC1 in a secondary solvent at room temperature. The mixture was searched until all starting materials were judged to be depleted by (LCB; 3: 7) by TLC. After 4 minutes, the dead volatiles were removed under vacuum, and the product F3 ', which was obtained as a white solid tablet, was used directly without further purification. Step 4

HCI H2N

F3 is N-methylmorpholine (3.7 equivalents,

T

F 0.06 ml, d 0.920) treated in 2 ml without 99028.doc -109- 200536530

A solution of amine hydrochloride F3 (67 mg) in water dichloromethane and cooled to 0 ° C. Isocyanate (0.75 ml of a 0.2 M solution in toluene) was added dropwise, and the mixture was stirred overnight (temperature 0 to 25 ° C). The reaction mixture was diluted with 50 ml of dichloromethane and washed with 15 ml of aqueous 1MHC1 and 15 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexane; 1: 9 to 6: 4) to give the product F as a white solid. Calculated value of HRMS (FAB) C36H58N507S [M + H] 704.4057; experimental value 704.4071.

Preparation Example G

A solution of the acid 11 (60 mg) in 2 ml of anhydrous digas methane and 1 ml of anhydrous dmf was stirred at 0 ° C and treated with hatu (1.4 equivalents, 60 mg). Amine salt 12 (1.2 equivalents, 30 mg) was added, followed by n-methylmorpholine (4 equivalents, 0.05 mL, d 0.920). The reaction mixture was stirred overnight (temperature 0 to 25 C). All volatiles were removed under vacuum and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed 99028.doc -110- 200536530 with water (20 mL), aqueous imhci (i (^ liter), saturated aqueous sodium bicarbonate solution (10 mL), and brine (10 mL). The organic layer was Cover with magnesium sulfate to dehydrate, filter and concentrate under reduced pressure. The product G1 can be used directly without further purification. Step 2

A solution of hydroxyammonium amine 1) (0.112 mmol) in 10 ml of anhydrous dichloromethane was treated with Dess-Martin periodinane (2.0 equivalents, 95 mg). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was treated with a 1 M aqueous sodium thiosulfate solution (10 ml) and stirred for 5 minutes. A saturated aqueous sodium bicarbonate solution (20 ml) was also added and stirring was continued for another 10 minutes. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexane; 19 to 4: 6) to give the product G (63 mg; 80%) as a white solid. Calculated HRMS (FAB) C37H61N607 [M + H] 701.4601; experimental value 701.4614. Preparation ExampleΗ

step 1

99028.doc 111-200536530 A solution of the acid 11 (00¾ g) in 2 ml of dry dichloromethane and 1 ml of dry dmf was stirred at 0 ° C and treated with HATU (14 equivalents, 60 mg). Amine salt 13 (1.2 equivalents, 30 mg) was added, followed by N.methylmorpholine (4 equivalents, 0.05 mL, d 0.920). The reaction mixture was decanted overnight (temperature 0 to 25 ° C). All volatiles were removed under vacuum and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed with water (20 ml), aqueous 1MHci (10 * liters), saturated aqueous sodium bicarbonate solution (10 ml), and brine (10 ml). The organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The product H1 was used directly without further purification. Step 2

A solution of carbamide & & amine amine 1 (0.112 mol) in 10 ml of anhydrous monofluoromethane was treated with Distin Martin's iodoane (2.0 equivalents, 95 mg). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was treated with a 1 M aqueous sodium thiosulfate solution (10 ml) and stirred for 5 minutes. A saturated aqueous sodium bicarbonate solution (20 ml) was also added and stirring was continued for another 10 minutes. The mixture was extracted with dichloromethane (3 x 30 ml). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (gradient · acetone / hexane; 1: 9 to 45 j5) to give the product H (64 mg; 82%) as a white solid. Calculated value of HRMS (FAB) C37H61N607 [M + H] 701.4601; experimental value 701.4607. 1 Preparation example I 99028.doc -112- 200536530

A solution of the acid 11 (60 mg) in 2 ml of anhydrous digas methane and 1 ml of anhydrous DMF was stirred at 0 ° C and treated with HATU (1.4 equivalents, 60 mg). Amine salt 14 (1.2 equivalents, 32 mg) was added, followed by N-methylmorpholine (4 equivalents, 0.05 mL, d 0.920). The reaction mixture was stirred overnight (temperature 0 to 25 ° C). All volatiles were removed under vacuum and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was rinsed with water (20 mL), aqueous 1M HC1 (10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and brine (10 mL). The organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. Product 11 was used directly without further purification. Step 2

A solution of Hydroxylamine 11 (0.112 mmol) in 10 ml of anhydrous digas methane was treated with Diss-Martin periodinane (2.0 equivalents, 95 mg). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was treated with 1 M aqueous sodium thiosulfate solution (10 ml) 99028.doc -113-200536530 and stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (20 ml) was also added and stirring was continued for another 10 minutes. The mixture was extracted with methane (3 x 30 ml). The combined organic layers were dehydrated with magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (gradient: acetone / hexane; 1: 9 to 45:55) to give product 1 (64 mg; 80%) as a white solid.

Preparation Example J

step 1

A solution of acid 11 (60 mg) in 2¾ liters of anhydrous dichloromethane and 1 ml of anhydrous dmf was mixed at 0C and treated with ΗΑΤυ (ι · 4 equivalent, 60 mg). Amine salt 15 (1.2 equivalents, 31 mg) was added, followed by N-methylmorphine (4 equivalents, 0_05 mL, d 0.920). The reaction mixture was stirred overnight (temperature 0 to 2 5 C). All volatiles were removed under vacuum and the residue was dissolved in 50 ml of ethyl acetate. The organic layer was washed with water (20 ml), aqueous 1M HC1 (10 ml), saturated aqueous sodium hydrogen chloride solution (10 ml), and brine (10 ml). The organic layer was dehydrated with magnesium sulfate, filtered, and concentrated under reduced pressure. The product J1 was used directly without further purification. Step 2 99028.doc -114- 200536530 〇

NH

A solution of Dess-Martin periodinane (20 equivalents,% mg) in ⑺ml of anhydrous monochloromethane (hydroxylamine ⑺ (112 mmol)) was treated. Incubate the reaction / adduct for 30 minutes at room temperature. The mixture was treated with M aqueous sodium thiosulfate solution (10 ml) and stirred for 5 minutes. A saturated aqueous sodium bicarbonate solution (20 liters) was also added and stirring was continued for another 10 minutes. Take the mixture with digas methane). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (gradient · acetone / hexane; 1: 9 to 45:55) to give the product J (57 mg; 71%) as a white solid. hrms (fab) CwHh ^ CMM + H] calculated 713 4601; experimental value 713.46〇7. The present invention relates to novel Hcv protease inhibitors. This availability can be demonstrated in its ability to inhibit HCV NS3 / NS4a serine proteases. The general procedure for this type of certification is illustrated by the following in vitro assays. Determination of HCV protease inhibitory activity: Spectrophotometric determination:

The procedure described in Biochemistry, 270 (1999) 268-275, the disclosure of which is incorporated herein by reference, is used for the spectrophotometric determination of serine proteases of the compounds of the present invention. The assay is based on the proteolysis of chromogen esters suitable for continuous monitoring of HCV NS3 protease activity. This substrate is derived from the p-position of the NS5A-NS5B junction sequence (Ac-DTEDVVX (NVa), where again = eight or P), using four different chromophore alcohols (3- or 4-nitrophenol, 7 -Hydroxy-4-methyl-coumarin or 4-phenylazobenzene 99028.doc -115-200536530 phenol), esterifying its c-terminal carboxyl group. The synthesis, characteristics, and applications of these novel spectrophotometric ester substrates are explained below for high-throughput screening and detailed kinetic evaluation of HCV NS3 protease inhibitors. Materials and Methods: Materials: from Sigma Chemical Company (St. Louis, Missouri)

Chemical reagents were obtained in buffer solutions related to the assay. Peptide synthesis reagents were obtained from Aldrich Chemicals, Novabiochem (San Diego, California), Applied Biosystems (Foster City, California), and Perseptive Biosystems (Framingham, Massachusetts). The peptides were synthesized manually or on an automated ABI Model 431A synthesizer (available from Applied Biosystems). The UV / VIS spectrometer LAMBDA 12 was obtained from Perkin Elmer (Norwalk, Connecticut), while the 96-well UV culture plate was obtained from Corning (Corning, New York). Preheat blocks are available from USA Scientific (Ocala, Florida), and 96-well culture plate rotators are available from Labline Instruments (Melrose Park, Illinois). A Spectramax Plus microtiter plate reader with a monochromator was obtained from Molecular Devices (Sunnyvale, California).

Enzyme preparation: By using a previously published procedure (D.L. Sali et al., Biochemistry, 37 (1998) 3392-3401), a recombinant heterodimer HCV NS3 / NS4a protease (line la) was prepared. Protein concentration was determined by the Biorad dye method using a recombinant HCV protease standard previously quantified by amino acid analysis. Before starting the assay, use a Biorad Bio-Spin P-6 prepackaged column to determine the buffer solution (25 mM MOPS pH 99028.doc -116- 200536530 6.5, 300 mM NaCH, 10% glycerol, 0.05% lauryl maltose Glycosides, 5 μM EDTA and 5 μM DTT) exchange enzyme storage buffer solution (50 mM sodium phosphate pH 8.0, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside and 10 mM DTT). Synthesis and purification of substrates: Synthesis of substrates was performed as reported by R. Zhang et al. (In the same book), and by using draft standards (K. Barlos et al., Int. J. Pept. Protein Res., 37 (1991), 513-520), Fmoc_Nva-OH was anchored to 2-chlorotrityl chloride resin to launch. Fmoc chemistry was then used to assemble the peptides manually or on an automated ABI 43 type 1 peptide synthesizer. Treated by 10% acetic acid (HOAc) and 10% trifluoroethanol (TFE) in dichloromethane (DCM) for 30 minutes, or by 2% trifluoroacetic acid (TFA) in dichloromethane (DCM) After 10 minutes of treatment, N-acetylated and fully protected peptide fragments were excised from the resin. Evaporate the mixed filtrate and DCM rinse solution azeotropically (or repeat the extraction with Na2CO ^ X solution) to remove the acid used in the cut. The DCM was dehydrated over Na2S04 and evaporated. Standard acid-alcohol coupling procedures (K. Holmber et al., Acta Chem. Scand., B33 (1979) 410-412) were used to assemble the S substrate. The fragment was dissolved in anhydrous anhydropyridine (30-60 mg / ml), and 10 mole equivalents of chromophore and a catalytic amount (0.1 equivalent) of p-toluenesulfonic acid (pTSA) were added thereto. Dicyclohexylcarbodiimide (DCC, 3 eq.) Was added to initiate the coupling reaction. Product formation was monitored by HPLC and the reaction was found to be complete after 12-72 hours at room temperature. The pyridine solvent was evaporated under vacuum and further removed by azeotropic evaporation with toluene. The peptide ester was deprotected with 95% TFA in DCM for 2 hours, and extracted three times with anhydrous diethyl ether to remove excess chromophore. Purify the deprotected substrate by reverse-phase HPLC on a C3 or 99028.doc -117- 200536530 C8 column using a 30% to 60% acetonitrile gradient (using 6 column volumes). The overall yield after HPLC purification may be approximately 20-30%. Molecular mass can be verified by electrospray ionization mass spectrometry. Store the substrate in dry powder under dry conditions. Substance and product spectrum: In a pH 6.5 measurement buffer solution, the spectrum of the substrate and the corresponding chromophore product was obtained. At the best off-peak wavelength (340-nm for 3-Np and HMC, 370-nm for PAP, and 400-nm for 4-Np), multiple dilutions were used to determine the extinction coefficient in a 1-cm cuvette. The optimal off-peak wavelength is defined as the wavelength between the substrate and the product that produces the largest graded difference in absorbance (product OD-substrate OD / substrate OD). Protease assay: HCV protease assay was performed at 30 ° C using 200 microliters of the reaction mixture in a 96-well microtiter plate. Assay buffer solution conditions (25 mM MOPS pH 6.5, 300 mM NaCl, 10% glycerol, 0.05% lauryl maltoside, 5 μM EDTA and 5 uM DTT) are the most suitable for NS3 / NS4a heterodimers (DL Sali et al. , In the same book). Typically, a 150 microliter mixture of buffer solution, substrate and inhibitor is placed in the well (final DMSO concentration of $ 4% v / v) and allowed to pre-incubate at 30 ° C for approximately 3 minutes. The reaction was then started using 50 microliters of pre-warmed protease (12 nM, 30 ° C) in the assay buffer solution (final volume 200 microliters). Throughout the measurement length (60 minutes), use a Spectromax Plus microtiter disk reader equipped with a monochromator at the appropriate wavelength (340 nm for 3-Np and HMC, 370 nm for PAP, and 4 -Np is 400 nm), monitoring the change in absorbance of the culture plate (acceptable results can be obtained with a plate reader using cut-off filter paper). At a suitable wavelength, it is used as a control group for non-enzymatic hydrolysis 99028.doc -118- 200536530 == white monitor the nitrogen bond between Nva and the cap of chromophore ~, use. In the 30-fold mass concentration range (~ 6-200 μM), the evaluation of the kinetic parameters was performed. The linear velocity was used to determine the muzzle velocity, and the data were matched to the Miehaelis_Menten equation by using the non-sexual regression analysis to obtain the mechanics f_ae Fit i i, K. Raner). Calculating turnover (kcat) assumes that the enzyme is completely active. Evaluating inhibitors and inactivating agents ... At a fixed concentration of enzymes and substrates, the Miehaeiis_Menten formula privately reorganized for competitive inhibition kinetics, / ¥ 1-1 + [1]. / (1 ^ (1 + [8] ./;^)), V () / Vi is plotted against the inhibitor / Chendu ([I].), And the competitive inhibitor Ac_D_ (D_Gla) is determined experimentally. Inhibition constants (Ki) of LI- (Cha) -C-OH (27), Ac-DTEDVVA (Nva) -OH, and DTEDVVP (NVa) -OH, where v. Is the uninhibited muzzle velocity 'Vi is the muzzle velocity in the presence of an inhibitor at any particular inhibitor concentration' and [S]. Is the concentration of substrate used. Linear regression was used to fit the obtained data and the resulting slope was 1 / (Ki (1+ [s] c) / Km) to calculate the Ki value. The Ki * values (in nanomoles) obtained for some compounds of the invention are shown in Table 2 below. Table 2 Registered compounds Ki * (nM) 1 Kyosuke ° YNH ° 0 13 99028.doc 119- 200536530

Table 2A lists additional compounds of the invention and their activities:

Table 2A

99028.doc -120- 200536530

99028.doc 121-200536530

99028.doc

122- 200536530

Ming, but 孰 ...: The specific embodiments are described together in an attempt to bring all such changes, modifications: changes, crossovers, modifications and other changes within the scope. And changes fall within the spirit of the present invention

Claims (1)

200536530 10. Scope of patent application: 1 · A compound, or the enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate of the compound, or the compound A pharmaceutically acceptable salt, solvate or ester, the compound has a common structure as shown in Formula 1: R1 is fluorene, OR8, NR9R10, or CHR9R10, wherein R9 and R10 may be the same or different and are selected from fluorene, alkyl-, alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl The group consisting of-, cycloalkyl_, heterocyclyl_, aralkyl_, and heteroaralkyl, or R9 and Rig in NR9R1G are connected to each other, so that NR9R1G forms a four to eight membered heterocyclic ring, and the same R and R in cHR9Ri0 are connected to each other to make CHR9R1g form a four-to-eight-membered ring courtyard; R2 and R3 may be the same or different and are selected from H, alkyl, heteroalkyl, alkenyl, and heteroene Group consisting of alkynyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; γ is selected from the following: 99028.doc 200536530 # Where G is NH or Ο; and R15, R16, r17, R18, R19, R20, R21, R22, R23, R24 and R25 may be the same or different and are selected from H, alkyl, heteroalkyl, alkenyl , Heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,-heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl group, or (i) Rl7 * Rl8 each other Connected to form a three- to eight-membered cycloalkyl or heterocyclic group; (ii) similarly, R15 * Ri9 is connected to each other to form a four-to-eight-membered heterocyclic group; "Four to eight members", heterocyclic groups; (iv) Similarly, and R2O are connected to each other to form a four, = i eight member 99028.doc 200536530; (v) Similarly, R22 and R23 are connected to each other to form Three to eight membered cycloalkyl or four to eight membered heterocyclyl; and (Vi) likewise, R24 and r25 are connected to each other to form a two to eight membered cyclohexyl or four to eight membered heterocyclyl; twenty three. Each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic group may be unsubstituted or may be substituted with one or more parts, respectively, which is selected from the group consisting of hydroxy, alkoxy, Aryloxy, thio, alkylthio, arylthio, amine, amidino, alkylamino, arylamino, alkanesulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl , Heteroaryl, alkylsulfonamido, arylsulfonamido, ketone, carboxyl, alkoxycarbonyl, carboxyamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylurea, A group consisting of arylureido, hydrogen, cyano, and nitro. For example, the compound of claim 1, wherein R1 is NR9r10, and Han 9 is H, R1 (^ Η: Ge Ri, where R1 is H, alkyl, aryl, heteroalkyl, heteroaryl:% alkyl, alkane -Aryl, alkyl_heteroaryl, aryl_alkyl, alkenyl, fastyl or heteroaryl-alkyl. The compound of claim 2 wherein R) 4 is selected from the group consisting of :, / ,, / ,, 1-4 1'3 1 · 3 1-3, 99028.doc 200536530 99028.doc -4- 200536530 5. The compound of claim 1, wherein R3 is selected from the group consisting of: 99028.doc 200536530 Wherein R31 is OH or 0-alkyl; and R32 is Η, C (0) CH3, C (0) 0tBu or C (0) N (H) tBu. 6. The compound of claim 5, wherein R3 is selected from the group consisting of: 99028.doc 200536530 • 7. The compound of claim 1, wherein G is NH. 8. The compound of claim 7, wherein Y is selected from the group consisting of: 99028.doc 200536530 ? 15 Ά ^ 1, /, R-Yihachi rl > RU18? 16 S, / 17 R18 Where R15, Rb, R17, R18 r19 r20, r21, r22 r23, R and R are selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaryl Alkyl groups, or (i) Ri > nRl8 are connected to each other to form a three to eight membered cycloalkyl or heterocyclic group; (ii) Similarly, RlqaRl9 is connected to each other to form a four to eight membered heterocyclic group; (iii) the same Ground, RlyuR16 is connected to each other to form a four to eight membered heterocyclic group; and (iv) is similarly connected to r20 to form a four to eight membered heterocyclic group; wherein each alkyl group, aryl group, heteroaryl group, ring The alkyl or heterocyclic group may be unsubstituted, or may be substituted with one or more parts, respectively, as required, the part is selected from the group consisting of alkyl, alkoxy, aryloxy, thio, thio, and arylthio. Amino, Amine, Amido, Alkylamino, Arylamino, Alkylsulfonyl, Arylsulfonyl, Sulfonamido, Alkyl, Aryl, Heteroaryl, Alkylsulfonium 99028.doc 200536530 Amine, arylsulfonamido, ketone, carboxyl, alkoxycarbonyl, carboxyamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen Of cyano and nitro. 9. The compound of claim 8 wherein the portion: Y32 is selected from the group consisting of: 10. The compound of claim 8 wherein Y is selected from: 99028.doc 200536530 99028.doc -10- 200536530 11. Compound as claimed in claim 1 Is selected from the following structures: 1 2 · The compounds of claim 1 are listed as: 99028.doc -11-200536530 99028.doc -12- 200536530 R3 is selected from the group consisting of: 99028.doc -13-200536530 〇 CHa ^ CHa OH C〇2H c〇2h This section: 22 p23 R25 ^. Selected from And Y is selected from: 99028.doc -14- 200536530 13. A pharmaceutical composition comprising, as an active ingredient, at least one compound as claimed in claim 1. 99028.doc -15-200536530 14. The pharmaceutical composition of Shiming seeking item 13 is used to treat HCV-related diseases. 15 The pharmaceutical composition of Shiming seeking item 1 * additionally includes at least one pharmaceutically acceptable carrier. 16. The pharmaceutical composition according to claim 15, further comprising at least one antiviral agent. 1 7. The pharmaceutical composition according to item 6, further comprising at least one interferon. 18. The pharmaceutical composition of claim 17, wherein the at least one antiviral agent is ribavirin, and the at least one interferon is cardiac interferon or polyethylene glycolized interferon. 19. The use of a compound as claimed in claim 1 in the manufacture of a medicament for the treatment of a condition related to hcv. 20. A method of preparing a pharmaceutical composition for treating a related condition, the method comprising bringing into close physical contact with at least one compound as claimed in claim and at least one pharmaceutically acceptable carrier. 21 · —A compound exhibiting HCV protease inhibitory activity, or the enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate of the compound, or the presence of the compound A pharmaceutically acceptable salt, lotion or vinegar, the compound is selected from compounds having the structure: 99028.doc -16-200536530 99028.doc 17- 200536530 99028.doc 18- 200536530 Ya 1 ^ QNH 0 Ya ΝΗ 1 > ^ s ^ XNH Human 々N% Human 々: AH H I. ^ NH Human 々NH 1 〇γΝΗ □ / v ^ Human 々: Human 々: a ^ rWv Human 々:. < 5 ◦ &^; ^ ΝΗ 1 ~~ 1 person 4:% 99028.doc 19- 200536530 99028.doc 20- 200536530 99028.doc -21-200536530 99028.doc 22- 200536530 99028.doc -23-200536530 99028.doc 24- 200536530 99028.doc 25- 200536530 99028.doc 26- 200536530 99028.doc 27- 200536530 99028.doc Η ίί ^ JL Μ Ν ^ γΝΗ2 νη2 V Η ΝΗ2 28- νη2 200536530 Χ; τ: 丨 | 1 X γ〇γΝΗ II ^ Χ] ΝΗ 1 泰 ο ^ νη ο.χ / Ο Τ croc II 1 1 X 1 〇 ° γΝΗ ii 6x ΟγΝΗ Μ 暴暴 XO ^ NH C ^ XV is ill 〇., 〇 ° ΥΝΗ 1 1 ofiNH II χχ 〇5 ^ NH II 〇5 ^: H III ox / o ° YNH 1 1 > V " 〇0 V ° o ^ nh f) fN, NH 1 X ^ 〇 ° Vp YAF〉 ^ s ^ < NH 99028.doc 29- 200536530 99028.doc 30- 200536530 99028.doc -31-200536530 99028.doc 32- 200536530 99028.doc Οχ / ΝΗ Ο, ο II (Ν— ^ ΝΗ 〇άΝ- Ο V ο ν〇 < ι >- ο V 〇 〇 〇 ΝΗ and X 』 0bab 0 ~ ΝΗ, ΝΗ Ο ν ο Ν, δ V 〇 meaning, 4 Ο 丫 ΝΗ ^ ΝΗ < Τ Ya Τ Vs ^^ 〇 V 〇 Ο ν Ο, parent JYN ^, ΝΗ isT " tr YA YA 0 V 0 Ο ^, ΝΗ I 〇 丫 ΝΗ ΝΗ ο V Ο Ο ~ ΝΗ) Υί Ν Ν I I Ο V ο Righte X 』 „; ° τ; -33- y " ττ 丫 > τ ό V ό ° ν〇 ΟγΝΗ ΊΓ >-^ / νη 200536530 99028.doc 34- 200536530 22 · A pharmaceutical composition for treating HCV-related disorders, the composition comprising a therapeutically effective amount of one or more compounds as claimed in claim 21 'and a pharmaceutically acceptable carrier. 23. The pharmaceutical composition according to claim 22, further comprising at least one antiviral agent. 24. The pharmaceutical composition of claim 23, further comprising at least one interferon or a PEG-interferon alpha co-roller. 25. The pharmaceutical composition of item 24, wherein the at least one antiviral agent is ribavirin, and the at least one interferon is ... an interferon or a polyethylene glycolized interferon. 26. The use of a compound as claimed in claim 21 in the manufacture of a medicament for the treatment of conditions associated with the hepatitis C virus. 2 7 · —Such as a request! The compound is used for the manufacture of a medicament for regulating hepatitis C virus bait. Ν) Protease activity. 28 ·-Kind of like a request! The use of a compound for the manufacture of a medicament for the treatment, prevention or amelioration of one or more symptoms of hepatitis. Use of 29J claim 28 ', wherein the hcv protease is a protease 30. Use of claim 29, wherein HCVNS3 / NS4a protease. 31.-Use of a compound such as 凊! In the manufacture of a medicament that modulates the processing of a c polypeptide. Disease reading: Chemical compounds are used in the manufacture and treatment of Hcv-related disorders. The compound is selected from the group consisting of: 99028.doc • 35- 200536530 99028.doc 36- 200536530 7. Designated Representative Map: (I) The designated representative map of this case is: (none) (II) The component symbols of this representative map are simply explained: Φ 8. If there is a chemical formula in this case, please reveal the best display Inventive chemical formula: 99028.doc